The use of selective serotonin reuptake inhibitors (SSRIs) is common among hemodialysis patients who receive treatment for depression. However, studies on the efficacy of SSRIs in patients on chronic hemodialysis are few and have led to conflicting results. The present systematic review aims to evaluate, in randomized, controlled studies (RCSs), the efficacy of SSRI administration in reducing symptoms of depression in patients on chronic hemodialysis when compared with placebo or psychological interventions. : Research was run on December 2023 in the following databases: Ovid MEDLINE (1985 to present); Ovid EMBASE (1985 to present); Cochrane Library (Wiley); and PubMed (1985 to present). The primary outcome was the frequency and severity of the symptoms of depression assessed through the Beck Depression Inventory (BDI) or the Hamilton Depression Rating Scale (HAMD). The secondary outcome was the prevalence of adverse events. : Seven studies totaling 433 patients were included. The number of patients in each individual study ranged from 13 to 120. The length of studies ranged from 8 weeks to 6 months. Heterogeneous data precluded informative meta-analysis. Three studies compared sertraline with a placebo. Of these, two demonstrated that sertraline was better than the placebo in reducing the symptoms of depression while one showed no statistically significant differences between sertraline and the placebo. One study, comparing fluoxetine with a placebo showed that the symptoms of depression did not differ significantly at 8 weeks. In another study, escitalopram administration led to a significantly greater reduction in the Hamilton Depression Rating Scale score compared to a placebo, as well as in the Hamilton Anxiety Rating Scale score. In one study, citalopram and psychological interventions were both effective in reducing the symptoms of depression and anxiety and, in another study, sertraline was modestly more effective than CBT at 12 weeks in reducing the symptoms of depression. : SSRIs may be effective in reducing the symptoms of depression in patients on chronic hemodialysis. SSRI administration, at the dosage used in the studies included in the present systematic review, seems safe in most hemodialysis patients. However, the paucity of studies and the limited number of patients included in the trials may suggest that further randomized, controlled studies are needed to determine if SSRIs may be used routinely in daily clinical practice in such a population.