Benadryl (diphenhydramine) and Zyrtec-D (cetirizine; pseudoephedrine) generally should not be taken at the same time as they both contain an antihistamine.

The active ingredient in Benadryl is diphenhydramine, a 'first-generation' antihistamine, while the active ingredients in Zyrtec-D are cetirizine, a 'second-generation' antihistamine, and pseudoephedrine (nasal decongestant).

Taking both Zyrtec-D and Benadryl at the same time would be considered a therapeutic duplication, potentially increasing the risk of side effects.

However, as per your question, you could safely take Benadryl first, then take Zyrtec-D 12 hours apart.

Benadryl has a short duration of action, around four to six hours for most individuals. 12 hours after taking Benadryl would typically be enough time for the effects of the drug to wear off, making it safe to take Zyrtec-D.

Section Summary
Benadryl and Zyrtec-D generally shouldn't be taken at the same time as they both contain antihistamines. Taking Benadryl first, and Zyrtec-D 12 hours later, is safe for most individuals.

Antihistamines Together

As stated above, taking both Benadryl and Zyrtec-D in considered duplicate therapy as they both contain antihistamines (even though they are different drugs).

Antihistamines work by binding to H1 (histamine-1) receptors in the body, preventing histamine from binding to them and producing the allergy symptoms we are all well aware of (e.g. runny nose, sneezing, itching).

Antihistamines do a pretty good job at binding to H1-receptors. Taking one antihistamine after another won't typically result in greater symptom control, as histamine receptors are already bound by the first-antihistamine you took.

Taking two (like Benadryl and Zyrtec-D) together would likely only increase antihistamine related side effects, such as:

  • Sedation
  • Drowsiness
  • Dry mouth
  • Dry eyes
  • Constipation
  • Urinary retention
  • Confusion (uncommon)

Now, there may be times where your doctor recommends taking two antihistamines close together in certain situations.

For example, they may instruct you to take Benadryl as needed, to help stem an allergic reaction, even if you already take antihistamines daily, like Zyrtec-D.

Studies aren't conclusive, but Benadryl may do a better job at reducing the inflammatory response to allergens than other antihistamines, making it beneficial to use in appropriate situations (e.g. for a bee sting).

So, while you shouldn't make it a habit of combining Benadryl and Zyrtec-D, there are times where it is okay.

Section Summary

Taking two antihistamines at the same time generally won't result in better effects and may increase the risk of side effects. However, Benadryl may be recommended for you to take if you are having an allergic reaction.

About Zyrtec

Zyrtec (cetirizine) is a 'second-generation' antihistamine, indicated for the treatment and prevention of perennial allergies, seasonal allergies and hives.

'Second-generation' antihistamines include:

  • Zyrtec
  • Allergra (fexofenadine)
  • Claritin (loratadine)

'Second-generation' antihistamines differentiate themselves from 'first-generation' antihistamines in a few key areas, including duration of action and sedative side effects. One dose will typically last around 24 hours and have a low incidence of sedation.

However, at indicated doses (5mg and 10mg), Zyrtec has a higher incidence of sedation than other second-generation antihistamines, such as Allegra (fexofenadine) and Claritin (loratadine).

Nevertheless, it still causes less sedation than older, 'first-generation antihistamines' such as Benadryl.

Zyrtec is taken once daily, with an onset of action around one hour.

About Benadryl

Benadryl (diphenhydramine) is a 'first-generation', sedating antihistamine (H1-blocker) of the ethanolamine class.

Due to the sedative properties of Benadryl, it is a common ingredient in over the counter sleep aid products, like ZzzQuil.

It also has potent "drying" effects in many, which is why it causes dry mouth, dry eyes, and constipation.

The onset of action of Benadryl is around 15-30 minutes after taking by mouth, with peak effects occurring 1 to 3 hours later.

The duration of action is around 4 to 6 hours, with this being prolonged in the elderly and in those with liver disease.


  • Benadryl and Zytec-D both contain antihistamines and generally should not be used together.
  1. ClinicalKey: Lithium Monograph. ClinicalKey (Subscription Required)
  2. Time-dependent inhibition of histamine-induced cutaneous responses by oral and intramuscular diphenhydramine and oral fexofenadine. PubMed
  3. Zyrtec-D Monograph. ClinicalKey (Subscription Required)