Although women may be particularly susceptible to the damaging effects of chronic cigarette smoking, evidence indicates that they may have more difficulty in maintaining smoking cessation than men. Given women's reduced response to nicotine replacement and other traditional treatments to habitual cigarette smoking, more targeted pharmacotherapy and intervention strategies may be necessary to improve their quit rates. Preliminary data by our group and others indicate that the opioid antagonist naltrexone may be an effective adjunctive pharmacotherapy approach for female smokers. The purpose of the proposed study is to conduct a randomized clinical trial to compare adjunct treatment with 50 mg oral naltrexone vs. placebo in conjunction with standard smoking cessation treatment with nicotine patch and counseling. Participants (N=324) will be randomized to receive either naltrexone or placebo starting one week prior to the quit date (25 mg for three days; 50 mg thereafter) and continue for 12 weeks after the quit date. The effects of naltrexone will be evaluated during the pre-quit date period, initial smoking cessation, relapse prevention, and at one year follow-up. It is hypothesized that sex will moderate the effects of naltrexone on outcome, with naltrexone improving prolonged abstinence quit rates in women but not in men. The secondary goal will be to elucidate the mechanism underlying women's treatment response to naltrexone. Weight (relative weight gain and weight concerns) and smoking-related variables (reduced cigarette pleasure, taste, craving and relief of negative withdrawal affect) may be important factors by which naltrexone improves quit rates in women. Medication compliance, psychosocial stress and levels of naltrexone's metabolite, 6-B-naltrexol, will also be examined. In sum, the proposed clinical trial will provide a comprehensive study of sex differences in response to adjunct treatment with naltrexone for smoking cessation. Given the public health concerns and significant health consequences of women's continued high rates of smoking, the proposed study may provide important information on a novel treatment strategy targeting the endogenous opioid system to selectively aid in women's smoking cessation.