Objective: To evaluate the effect of doxepin hydrochloride 5% cream on reducing pruritus in burn scar patients compared to a placebo cream. Method: We conducted a multicenter triple-blind randomized clinical placebo-controlled crossover trial in which burn patients ≥18 years with an itch intensity ≥3 on a Visual Analogue Scale (VAS) were randomized between a doxepin-placebo or placebo-doxepin treatment protocol. Patients used each cream during two weeks with a wash-out period of one week in between. Primary outcome was change in itch intensity in two weeks’ time using the VAS. Secondary outcome included the impact of itch (Burn Itch Questionnaire). Other parameters were the use of hydrating cream, silicon treatment, pressure garments, and other antipruritic medication. Results: Twenty-seven patients were included. The change in itch intensity (VAS) was not different during the doxepin and placebo period (p = 0.994); neither the doxepin cream nor placebo cream reduced itch intensity. However, based on the Burn Itch Questionnaire, we observed a statistically significant decrease in itch intensity and improvement in impact scores in both treatment groups, but no difference in the degree of reduction between the groups. Conclusion: Doxepin cream was not effective in reducing pruritus in our burn patient study population.