This study examined the efficacy of transdermal nicotine in postmenopausal smokers, and whether a history of depression or hormone replacement therapy (HRT) moderated smoking cessation outcomes. Postmenopausal smokers (N=152) received intensive smoking cessation counseling and were randomly assigned to use either a 21-mg nicotine patch for 3 months, with a 1-month taper, or a placebo patch. The primary outcome was biochemically validated 7-day point prevalence smoking abstinence during treatment (i.e., 1, 2, 6, and 12 weeks after the quit date) and 1 year after study medication was discontinued. Subjects who received transdermal nicotine were significantly more likely than placebo-treated subjects to remain abstinent from smoking during treatment, but not at the 1-year follow-up. The majority of subjects (>50%) in both groups accurately identified their treatment assignment. History of depression was associated with a decreased likelihood to abstain from smoking throughout the study. HRT did not moderate smoking outcomes. These data indicate that transdermal nicotine may provide short-term benefits for smoking cessation in postmenopausal women. However, efforts are needed to improve long-term abstinence rates and smoking outcomes among women with a history of depression.