OBJECTIVE Major depressive disorder (MDD) patients often experience impaired sexual satisfaction (ISS) and poor quality of life (QOL). Selective serotonin reuptake inhibitors (SSRIs), the first-line treatment for MDD, can cause sexual dysfunction, potentially worsening ISS and QOL. This study examined the impact of MDD and the SSRI citalopram on sexual satisfaction and QOL in level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (July 2001-September 2006). METHOD A retrospective analysis was conducted of the change in sexual satisfaction, as measured by item 9 of the Quality of Life Enjoyment and Satisfaction Questionnaire, the primary outcome measure, in 2,280 patients with DSM-IV-TR-defined MDD who were treated with citalopram for 12 weeks. The Quick Inventory of Depressive Symptomatology-Self Report was used to evaluate the impact of depression ratings on impaired sexual satisfaction and on QOL. RESULTS Impaired sexual satisfaction was present in 64.3% of MDD patients at pretreatment, but that percentage declined to 47.1% at posttreatment with citalopram (P < .0001). Those who achieved remission had less ISS and better QOL. The prevalence of ISS in remitters was 21.2% versus 61.3% in nonremitters (P < 10(-8)). The mean ± standard deviation score for remitters increased from 2.32 ± 1.16 to 3.44 ± 1.23 (P < 10(-8); Cohen d = 0.81 [large effect size]), whereas in nonremitters it increased only from 1.99 ± 1.08 to 2.19 ± 1.19 (P < 10(-8); Cohen d = 0.16). The difference between remitters and nonremitters was highly significant (P < 10(-8)). Regression analyses at pretreatment and posttreatment demonstrated significant associations between depressive symptoms and ISS (P < .0001) and between ISS and lower QOL (P < .0001) as well as an association between citalopram and increased probability of ISS and a poorer QOL in patients who continue to have moderate-to-severe depression. CONCLUSIONS A majority of MDD patients have impaired sexual satisfaction, a symptom associated with poor QOL. Despite the sexual side effects of the SSR citalopram, treating depression to full remission was associated with improvements in sexual satisfaction and QOL. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00021528.