The unique feature of this study is the double-blind comparison of three interventions for patients who did not decrease their smoking by 50% during the prequit phase. One-third were continued on nicotine patch, one-third received the nicotine patch plus bupropion, and one-third were switched to varenicline. Bupropion was titrated to 150 mg twice daily and varenicline to 1 mg twice daily. The treatment period lasted 12 weeks, and approximately 100 patients were in each group. At 12 weeks, the abstinence rate for treatment with nicotine patch alone was less than 7% for patients who had not decreased their smoking before the quit date, compared with 50% for those patients who had decreased smoking before the quit date. Patients who had bupropion added to the nicotine patch achieved a response rate of 19%, and patients who were switched to varenicline achieved a response rate of 12%, the latter effect not significantly different from the nicotine patch condition. At 6 months, among the patients who had not responded during the prequit phase, 7% of those on nicotine patch alone, 17% of those who received bupropion in addition, and 16% of those on varenicline were abstinent. Thus, the addition of bupropion to the nicotine patch for patients who did not respond quickly to patch alone significantly increased the response rate. Varenicline had longer-term effects that were also significantly better than the patch alone for nonresponding patients.