Sexual dysfunction commonly occurs with major depressive disorder (MDD). Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist antidepressant approved for the treatment of MDD in adults, was evaluated to determine its effects on sexual function. The primary study was a double-blind, randomized, controlled trial comparing vilazodone 20 and 40 mg/day with placebo; citalopram 40 mg/day was an active control (NCT01473381; http://www.clinicaltrials.gov). Post-hoc analyses evaluated change from baseline to week 10 on the Changes in Sexual Functioning Questionnaire (CSFQ); no inferential statistics were performed. CSFQ scores increased for women [1.2 (citalopram) to 3.0 (vilazodone 40 mg)] and men [1.2 (vilazodone 40 mg) to 3.5 (placebo)] in all treatment groups. Greater changes in CSFQ scores were seen in responders [women: 2.33 (citalopram) to 5.06 (vilazodone 40 mg); men: 2.26 (vilazodone 40 mg) to 4.35 (placebo)] versus nonresponders. CSFQ change from baseline was small for patients with normal baseline sexual function; in patients with baseline sexual dysfunction, CSFQ scores improved across groups [women: 2.35 (citalopram) to 4.52 (vilazodone 40 mg); men 2.83 (vilazodone 40 mg) to 6.43 (placebo)]. Across treatment groups, baseline sexual function improved in women and men, MDD responders, and patients with baseline sexual dysfunction.