The present study, a secondary analysis of published data, assessed (a) the influence of initial positive mood (PM) on smoking cessation and (b) whether smokers low in PM benefited from fluoxetine versus placebo for cessation. Euthymic adult smokers (N = 103) received 10 weeks of cessation treatment. Analyses showed a Time x PM interaction, indicating that higher baseline PM predicted decreased abstinence during treatment but increased abstinence afterward, mediated by time to dropout. Dichotomous initial PM interacted with drug, suggesting a benefit of fluoxetine for low-PM smokers. Results indicate that lower pretreatment PM may inhibit long-term cessation. Smokers with lower baseline PM may benefit from treatment that increases PM.