Kidney stones impose a large and increasing public health burden. Previous studies showed that hyponatremia is associated with an increased risk of osteoporosis and bone fractures, which are also known to be associated with kidney stones. However, the relation between hyponatremia and kidney stones is not known. To assess the relation between hyponatremia and kidney stones, we designed a matched case-control study by using the electronic health records of the MedStar Health system with more than 3.4 million unique patient records as of March 2016. Data were extracted for clinical factors of patients with kidney stones (cases) and those without kidney stones (controls). Cases (n = 20,199) and controls (n = 20,199) were matched at a 1:1 ratio for age, sex, race, and the duration of encounter window. Case and control exposures for each of the hyponatremia variables were defined by serum sodium laboratory measurements reported within the encounter windows, and divided into 3 categories: prior hyponatremia, recent hyponatremia, and persistent hyponatremia. In the final conditional logistic models adjusted for potential confounders, the risk of kidney stones significantly increased in both recent and persistent hyponatremia categories: prior hyponatremia odds ratio (OR) 0.93 (95% confidence interval [CI], 0.86-1.00); recent hyponatremia OR 2.02 (95% CI, 1.76-2.32); persistent hyponatremia OR 6.25 (95% CI, 3.27-11.96). In conclusion, chronic persistent hyponatremia is a significant and clinically important risk factor for kidney stones in patients in the U.S.