Abstract This short-term, double-blind, placebo-controlled, crossover study evaluated the effectiveness of 10% trolamine salicylate in a cream base as a topical analgesic compared with placebo. Fifty patients with pain and stiffness because of osteoarthritis in their hands participated in the study; 49 patients completed the study. Patients rated their pain and stiffness in the morning on awakening, and at 15, 30, 45, and 120 minutes after application of their study cream. Although the phases of this crossover study were separated by 1 week, a consistent period effect occurred. Because of these residual effects, the statistical results of period 1 become our focus as this period was free of carryover and period effects. A trend in favor of trolamine salicylate was seen 30 minutes following application of the study drug; at 45 minutes, use of trolamine salicylate was clearly better than placebo in achieving pain relief ( P = 0.0401; intent-to-treat). Two hours following a single application of the study drug, much of the drug effect had worn off. Trolamine salicylate was better (marginally significant) than placebo in time to peak pain relief ( P = 0.0674; intent-to-treat), in disappearance of pain ( P = 0.0435; intent-to-treat), and overall trend analysis. Stiffness relief was attained significantly earlier (35 minutes compared with 58 minutes) in the group treated with trolamine salicylate compared with placebo ( P = 0.0368; per protocol). No significant adverse effects were reported.