Diphenhydramine is a first-generation antihistamine and cetirizine is a second-generation antihistamine. They are both used for the treatment of allergy symptoms. The difference between the two drugs is that a first-generation antihistamine is more likely to cause side effects like drowsiness and to interact with other medications. Diphenhydramine is more similar to medications like brompheniramine, dimenhydrinate, doxylamine and chlorpheniramine. Cetirizine is more similar to loratadine.