INTRODUCTION: A paucity of data exists regarding the safety and effectiveness of combination treatment with varenicline and nicotine replacement therapy (NRT). METHODS: We reviewed the clinical experience of two groups of cigarette smokers enrolled in a residential tobacco treatment program: (a) patients receiving combination treatment with varenicline and NRT (N = 104) and (b) usual-care patients receiving treatment before the release of varenicline (N = 135). RESULTS: Demographic characteristics were similar between the two groups. Among smokers receiving varenicline and NRT, 71% used the nicotine patch with a mean dose of 32 mg/day (SD = 14) and 73% used at least two types of NRT. Adverse events were experienced by 39% (95% CI = 31%-49%) of patients receiving varenicline and NRT and by 59% (95% CI = 51%-67%) of usual-care patients during the residential program. A total of five patients (5%) discontinued varenicline due to adverse events, compared with one patient in the usual-care group. We did not observe a significant difference in the 30-day point prevalence smoking abstinence rate at 6 months between patients treated with varenicline and NRT (54%; 95% CI = 44%-64%) and usual-care patients (59%; 95% CI = 50%-66%). DISCUSSION: Our findings suggest that combination therapy with varenicline and NRT is safe and well tolerated among patients in a residential tobacco treatment program.