Purpose <p>The incidence and risk of serotonin syndrome associated with selective serotonin reuptake inhibitors (SSRIs) have increased. However, large-scale studies investigating this relationship remain limited. Therefore, this study aims to evaluate the signal detection between six SSRIs and serotonin syndrome, rank their relative risks, and propose practical preventive strategies.</p> Methods <p>This study utilized the global pharmacovigilance database, which systematically compiles adverse drug reaction reports from over 140 countries. The analysis focused on individuals diagnosed with serotonin syndrome associated with SSRIs, classified under the Anatomical Therapeutic Chemical code ‘N06AB’ and categorized into six types. A disproportionality analysis was conducted using the information component (IC) with IC_0.25 and the reporting odds ratio (ROR) with 95% confidence interval (CI) to assess the signal detection between serotonin syndrome and SSRIs.</p> Results <p>Among 35 million reports, 24,674 reports of serotonin syndrome were identified from 1968 to 2024, including 4,035 associated with SSRIs. Sertraline (24.46%) was the most frequently implicated SSRI. All SSRIs indicated a significant signal detection with serotonin syndrome, with citalopram exhibited the highest signal (ROR: 77.29 [95% CI, 71.63–83.40]; IC: 6.13 [IC₀₂₅, 6.01]). Hyperthermia and neurological manifestations were the most prevalent. The median time to onset was one day. Recovery rate was 62.21%, and mortality was 0.25%.</p> Conclusion <p>The findings underscore the potential signal detection between SSRIs and serotonin syndrome. Results also highlight the need to strengthen prevention and management to mitigate associated risks, while long-term studies on serotonin syndrome are essential for improving patient safety and optimizing treatment.</p>