Allergic reactions caused by external factors are treated with medicinal products containing antihistamines, therefore their action is delayed in time. Combination of antihistamines and fast-acting analgesics may help to reduce discomfort associated with cutaneous reactions. To evaluate efficacy and safety of the combination topical gel containing diphenhydramine hydrochloride 20 mg/g and lidocaine hydrochloride 10 mg/g over placebo in the treatment of local skin inflammatory and allergic reactions. A study was a single-centre, single-dose, randomized, double-blind, two-treatment, two-period, two-sequence cross-over clinical trial (n = 44) in healthy subjects. Local skin inflammatory and allergic lesions were induced by the provocative test with histamine in healthy subjects. For all parameters recorded with the Visual Analogue Scale (VAS), the area under the curve (AUC) was calculated and the peak itch intensity was noted for every subject in response to the skin prick test. The primary endpoint of the study was the difference in AUC calculated from the intensity of itch for test product A (diphenhydramine hydrochloride 20 mg/g and lidocaine hydrochloride 10 mg/g, gel) and placebo product B. The results revealed that itching intensity AUC was significantly greater for product B than for product A, on average by 2.05 points. A decrease in itching intensity was observed from the second minute after application of the test product. The study provided evidence for differences in efficacy between the product tested and placebo.