Varenicline carries a black box warning for neuropsychiatric adverse events. We examined varenicline use and past history of major depressive disorder (MDD) on depressive symptoms during smoking cessation. This is a secondary analysis of two smoking cessation studies in 152 postmenopausal women who received placebo or nicotine patch, or 78 women who received varenicline with relaxation. Lifetime history of MDD (LH-MDD) was assessed at baseline and women with current MDD were excluded. Center for Epidemiologic Study Depression scale (CESD) measured depressive symptoms at baseline, 6 and 12 weeks. Baseline CESD scores were 5.3 + 4.4. Those with a LH-MDD reported higher CESD scores (p > .001). Those taking varenicline reported lower scores over all time periods compared to nicotine or placebo (p < .01). The differences between varenicline and the other treatments remained when controlling for LH-MDD, indicating an independent effect. CESD scores were associated with concurrent smoking status (p < .001), and with withdrawal symptoms (p < .001). CESD score were lower in those receiving varenicline, whether this is due to an anti-depressant effect, subject selection, use of relaxation or another cause is unknown. Varenicline does not increase depressive symptoms during smoking cessation in postmenopausal women without current MDD. Subjects with a LH-MDD are susceptible to developing depressive symptoms during smoking cessation, regardless of pharmacologic aid. Pharmacologic aids did not increase depression symptoms in this select population of postmenopausal women without current depression. Smoking cessation does increase depressive symptoms in those with LH-MDD, though the degree of increase was not clinically meaningful.