Background: Psoriasis is a common disease which often requires long-term maintenance therapy. In psoriatic epidermis, the level of cyclic adenosine monophosphate ( cAMP) decreases. It has been reported that beta-blockers exacerbate existing psoriatic plaque and decrease the concentration of intracellular cAMP. Caffeine is a methylxanthine that inhibits phosphodiesterase enzyme and results in a higher concentration of intracellular cAMP. Objective: Evaluation of the efficacy of topical caffeine 10% in the treatment of psoriasis. Patients and methods: The patients were treated by topical application of 10% caffeine or placebo three times per day on the right or left side of the body ( randomly selected by flipping a coin). Thirty-nine patients with stable plaque psoriasis were included in a randomized, double-blind, placebo-controlled, right/left comparison. The patients visited every other week for a period of 8 weeks. Their Psoriatic Area and Severity Index ( PASI) scores were assessed at each visit. Results: The reductions in PASI scores measured at the four visits for the caffeine-treated group were 2.64 +/- 2.89, 4.47 +/- 3.62, 5.73 +/- 4.16, 6.58 +/- 4.40 and for the placebo-treated group the values were 1.45 +/- 2.32, 3.04 +/- 2.68, 4.02 +/- 3.36, 4.43 +/- 3.45, respectively. Comparing the corresponding results of the two groups, p values at the second, fourth, sixth and eighth week were 0.081, 0.083, 0.079 and 0.047, respectively. Based on presented p values, the treatment with caffeine is more effective than with placebo after 8 weeks ( p < 0.05), and the only side effect of caffeine is mild itching. Conclusion: Based on the results of the trial, topical caffeine is an effective, safe and inexpensive treatment for psoriasis, with a delay in action.