Objective: To examine the association between sexual functioning, depression and anxiety severity, and selective serotonin reuptake inhibitor (SSRI) use in adolescents.Methods: From September 2010 to December 2014, 15- to 20-year-old participants, either unmedicated or within a month of beginning SSRI treatment, completed the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and Changes in Sexual Functioning Questionnaire (CSFQ) at baseline and every 4 months for up to 2 years. The DSM-IV-TR was used to determine presence of psychiatric disorders. Data regarding use of medications and hormonal contraception were collected. Polymorphisms of the HTR2A and ABCB1 genes were genotyped. Linear mixed-effects regression models examined the association between depression and anxiety symptom severity, SSRI use, and sexual functioning, accounting for relevant covariates.Results: A total of 263 participants (59% female, mean ± SD age = 18.9 ± 1.6 years, 70% with major depressive disorder) contributed to this analysis. After adjusting for age, sex, and duration in the study, depression severity, but not anxiety severity, was associated with lower CSFQ total scores (β = -0.13, P < .0001) and lower arousal, orgasm, and pleasure subscale scores (all β = -0.03, P < .003). Higher SSRI doses were associated with lower orgasm subscale scores (β = -0.30, P < .03). Hormonal contraceptive use was associated with higher CSFQ total scores (β = 0.97, P < .003) and higher arousal (β = 0.25, P < .009), desire (β = 0.24, P < .001), orgasm (β = 0.27, P < .02), and pleasure (β = 0.15, P < .004) subscale scores. No significant genetic moderating effect was found.Conclusions: In adolescents, depression is associated with lower sexual functioning while SSRI use impairs orgasm.