Purpose <p>Observational evidence indicates an association between sleep disorders and the risk of nephrolithiasis (kidney stones), but whether this relationship reflects a causal effect remains uncertain. The causal relationship between genetically determined sleep disorders and the risk of nephrolithiasis using a two-sample Mendelian randomization (MR) approach was investigated.</p> Methods <p>This two-sample MR study utilized genome-wide association summary data for both sleep disorders and nephrolithiasis. The main analysis was conducted using the inverse variance weighted method, while confirmatory analyses employed the weighted mode, weighted median, and MR-Egger regression approaches to test for consistency and robustness. Heterogeneity among instrumental variables was evaluated using Cochran’s Q-test, and the potential for horizontal pleiotropy was assessed with the MR-Egger regression intercept. To further gauge the robustness and consistency of the findings, a leave-one-out sensitivity analysis was performed, systematically omitting each single-nucleotide polymorphism in turn.</p> Results <p>Genetically predicted sleep apnea was associated with nephrolithiasis (OR = 1.0032, 95% CI: 1.0011–1.0053, P = 0.0025) and nephrolithiasis intervention (OR = 1.0027, 95% CI: 1.0008–1.0046, P = 0.0057) and that combined sleep disorders were associated with nephrolithiasis (OR = 1.0042, 95% CI: 1.0014–1.0070, P = 0.0032) and nephrolithiasis intervention (OR = 1.0027, 95% CI: 1.0004–1.0050, P = 0.0240). The MR-Egger test indicated no pleiotropy, and the Q-test revealed no heterogeneity for the causal associations above. The MR-PRESSO test showed no horizontal pleiotropy among the tested SNPs for the identified causal associations. The leave-one-out analysis revealed similar results.</p> Conclusion <p>This MR study revealed causal associations between sleep disorders and nephrolithiasis. Further studies are needed to confirm these findings and elucidate the underlying mechanisms.</p>