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Purpose: Selective serotonin re-uptake inhibitors (SSRIs) are frequently used to treat premature ejaculation (PE) in men. We performed a Cochrane review to assess the efficacy of SSRI treatment for PE. Materials and Methods: We extensively searched a range of databases up to May 2020 and only included randomized controlled trials. Results: A total of 31 studies with 8,254 men were included in this analysis. We found that SSRI treatment probably improves self-perceived PE symptoms (defined as a rating of ‘better’ or ‘much better’; risk ratio [RR], 1.92; 95% confidence interval [CI], 1.66–2.23; moderate-certainty evidence) and satisfaction with intercourse (defined as a rating of ‘good’ or ‘very good’; RR, 1.63; 95% CI, 1.42–1.87; moderate-certainty evidence) compared to placebo. Furthermore, SSRI treatment likely improve participants’ self-perceived control over ejaculation (defined as rating of ‘good’ or ‘very good’; RR, 2.29; 95% CI, 1.72–3.05; moderate-certainty evidence) and probably lessens distress (defined as rating of ‘a little bit’ or ‘not at all’) about PE (RR, 1.54; 95% CI, 1.26–1.88; moderate-certainty evidence). SSRI treatment may increase IELT compared to placebo (mean difference, 3.09 minutes higher; 95% CI, 1.94 higher to 4.25 higher; low-certainty evidence). However, SSRIs may increase treatment cessations due to adverse events compared to placebo (RR, 3.80; 95% CI, 2.61–5.51; low-certainty evidence). Conclusions: SSRI treatment for PE appears to substantially improve a number of outcomes of direct patient importance such as symptom improvement, satisfaction with intercourse and perceived control over ejaculation when compared to placebo.