Many women diagnosed with a major depression continue or initiate antidepressant treatment during pregnancy. Both maternal stress and selective serotonin inhibitor (SSRI) antidepressant treatment during pregnancy have been associated with changes in offspring behavior, including increased anxiety and depressive-like behavior. Our aim was to investigate the effects of the SSRI fluoxetine (FLX), with and without the presence of a maternal depression, on affective behavior in male and female rat offspring. As reduced serotonin transporter (SERT) availability has been associated with altered behavioral outcome, both offspring with normal (SERT) and reduced (SERT) SERT expression were included. For our animal model of maternal depression, SERT dams exposed to early life stress were used. Perinatal FLX treatment and early life stress in dams (ELSD) had sex- and genotype-specific effects on affective behavior in the offspring. In female offspring, perinatal FLX exposure interacted with SERT genotype to increase anxiety and depressive-like behavior in SERT, but not SERT, females. In male offspring, ELSD reduced anxiety and interacted with SERT genotype to decrease depressive-like behavior in SERT, but not SERT, males. Altogether, SERT female offspring appear to be more sensitive than SERT females to the effects of perinatal FLX exposure, while SERT male offspring appear more sensitive than SERT males to the effects of ELSD on affective behavior. Our data suggest a role for offspring SERT genotype and sex in FLX and ELSD-induced effects on affective behavior, thereby contributing to our understanding of the effects of perinatal SSRI treatment on offspring behavior later in life.Copyright © 2020. Published by Elsevier B.V.