The effect of clonidine on smoking cessation was studied by randomly assigning 186 smokers in a double-blind fashion to either placebo or clonidine. Abstinence from smoking was reported more frequently by subjects receiving clonidine, but the difference was statistically significant only at the end of the first week (34.4% vs 21.5%; p less than 0.05). Bothersome side effects were common and resulted in the early discontinuation of the study medication by 23 of the subjects taking clonidine and eight taking placebo (p less than 0.05). Although this study did not demonstrate a significant effect of clonidine on smoking cessation, a beneficial trend was detected and therefore further trials with transcutaneous delivery of this agent in combination with behavior modification techniques are warranted.