OBJECTIVE: Hyponatremia is one of the most common electrolyte disorders in clinical practice and is frequently observed following thiazide use. Advanced age and female gender are implicated in the etiology of hydrochlorothiazide (HCTZ)-associated hyponatremia. There has also recently been mention of a genetic disposition. This study evaluated the genetic component, and particularly the clinical significance, of variants in the SLC12A3 gene in the development of hyponatremia in hypertensive patients using HCTZ-group diuretics. METHOD: Ninety-five patients presenting to the Tekirdağ Namık Kemal University nephrology clinic and receiving antihypertensive therapy including HCTZ for at least one month were examined. Peripheral blood specimens were collected from hyponatremic (n = 62) and non-hyponatremic (n = 33) individuals. Variants in the SLC12A3 gene were analyzed using next generation sequencing and were compared with the clinical data. RESULTS: A total of 947 variants were detected in the SLC12A3 gene, the majority of which were classified as of uncertain significance. Hyponatremia was determined at a higher rate in patients with c.506-276A>G (75.00%), c.282+492G>A (85.70%), c.282+499G>C (87.00%), c.282+495G>A (85.00%), and c.505+375G>A (92.30%) variants in particular. The risk of hyponatremia development increased 9.2-fold in the presence of the c.282+492G>A variant (OR = 9.243; 95% CI: 2.259-37.818; p = 0.002). CONCLUSION: In conclusion, we think that HCTZ-associated hyponatremia cannot be predicted by clinical and biochemical parameters alone, and that genetic factors should also be considered. Further multi-center prospective studies involving larger populations will clarify the clinical significance of variants in SLC12A3 and other genes and will make a significant contribution to individualized therapeutic approaches.