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It is unclear whether increasing the dose of varenicline beyond the standard dose of 2 mg/d would improve smoking abstinence.We examined the effect of 3 mg/d of varenicline on smoking abstinence among smokers who had reduced their smoking by 50% or more in response to 2 mg/d for at least 6 weeks but had not quit smoking. Of 2833 patients treated with varenicline, dosage of a subset of 73 smokers was increased to 3 mg/d after 6 weeks. We used a propensity score analysis involving multiple baseline covariates to create a comparative sample of 356 smokers who remained on 2 mg/d. All smokers received concurrent and similar smoking-cessation counseling.At 3 months, we found higher 7-day point prevalence smoking-abstinence rate in the 3-mg group (26%) than in the 2-mg group (11.5%, χ2 = 10.60, P < 0.001; risk ratio [RR], 2.3; 95% confidence interval [CI], 1.4–3.6). The difference in abstinence rates remained significant at the 6-month (P < 0.001; RR, 2.6; 95% CI, 1.6–3.9) and 9-month follow-up (P < 0.001; RR, 2.2; 95% CI, 1.4–3.3).A relatively small increase in the daily dose of varenicline seems to offer a benefit for those who are not able to achieve total abstinence after approximately 6 weeks of 2 mg/d.