The short (s) variant of the serotonin transporter gene linked functional polymorphic region (5-HTTLPR) is associated with depression. Stressful life events, gender, and race have been shown to moderate this association. Because features of mania/hypomania seem to constitute an indicator of higher severity of depression, we examined the relationship between 5-HTTLPR genotype and symptoms of mania-hypomania spectrum occurring over the lifetime in patients with major depression. The possible moderating role of gender in this relationship was taken into account. Two hundred twenty-two patients with unipolar major depression were genotyped for 5-HTTLPR and nine other representative polymorphisms, and were administered the Mood Spectrum Questionnaire, Lifetime Version (MOODS-SR). The manic-hypomanic (MH) component score was used for analysis. Using a linear model of the MH score as a function of genotypes and gender, controlling for age, severity of depression, and site, we found significant effects of gender (F = 8.003, df = 1, P = 0.005), of the interaction gender × genotype (F = 4.505, df = 2, P = 0.012), and of the baseline Hamilton score (F = 5.404, df = 1, P = 0.021), non-significant effects of genotype (F = 1.298, df = 2, P = 0.275), age (F = 0.310, df = 1, P = 0.578) site (F = 0.504, df = 1, P = 0.479). Significant associations were also detected at three other SNPs. The association between the manic/hypomanic component of the MOODS-SR and the polymorphisms of the 5-HTTLPR is moderated by gender. This finding is intriguing from a clinical point of view because women with unipolar disorder and the “ss” genotype seem to constitute a sub-group with higher severity of depression. These results should be considered tentative pending replication in other samples.