ObjectiveHyponatremia is a common electrolyte disorder among older adults that can cause serious adverse effects. The purpose of this study was to assess the risk of hyponatremia with the concurrent use of selective serotonin reuptake inhibitors (SSRIs) and thiazide diuretics in an older population. MethodsTwo retrospective nested case-control studies were conducted with exposure to an SSRI or a thiazide diuretic. Persons of interest were those enrolled in Medicare and who received parts A, B, and D benefits from 2017 to 2019 and who were receiving either an SSRI or thiazide diuretic. Cases were individuals with a diagnosis of hyponatremia. Controls had no documented history of hyponatremia. A logistic regression was conducted to determine the odds of hyponatremia. ResultsOf the 551,298 patients receiving a SSRIs, the mean age was 77.8 years (Standard Deviation (SD) +/- 8.0 years), 69% were female, and 91.23% were classified as White. We identified 701,007 individuals receiving a thiazide diuretic, with a mean age of 77.1 years (SD +/- 7.2 years), 60.2% female, and 82.72% White. The prevalence of hyponatremia was 10.4% in patients taking thiazides alone and 9.0% in those taking SSRIs alone. On the other hand, patients on both medications had a hyponatremia prevalence of approximately 13.0%. Among SSRI users, the adjusted odds ratio (OR) of hyponatremia with concomitant use of thiazide diuretics was 1.24 (95% Confidence Interval (CI): 1.22-1.26). For thiazide users, the adjusted OR of hyponatremia with exposure to SSRIs was 1.27 (95% CI:1.24-1.29). ConclusionThe concurrent use of thiazide diuretics and SSRIs is associated with an increased risk of hyponatremia in older populations.