BACKGROUND: Obesity and type 2 diabetes have been associated with an increased risk of kidney stones in observational studies, but the causality of these associations remains unestablished. We conducted a Mendelian randomization study to determine these associations. METHODS: Independent single nucleotide polymorphisms at the genome-wide significance threshold (p < 5 × 10) were selected as instrumental variables and were identified from meta-analyses of genome-wide association studies on body mass index (up to 806,834 individuals) and type 2 diabetes (228,499 cases and 1,178,783 non-cases). Summary-level data for the associations of exposure-associated SNPs with kidney stones were obtained from the UK Biobank study (3540 cases and 357,654 non-cases) and the FinnGen consortium (3856 cases and 172,757 non-cases). Causal estimates from two sources were combined using the meta-analysis method. RESULTS: Higher genetically predicted body mass index and genetic liability to type 2 diabetes were associated with an increased risk of kidney stones in both the UK Biobank study and FinnGen consortium. In the meta-analysis of results from the two data sources, the odds ratios of kidney stones were 1.33 (95% confidence interval, 1.17, 1.51; p < 0.001) per one standard deviation increase in genetically predicted body mass index (~4.8 kg/m) and 1.15 (95% confidence interval, 1.10, 1.20; p < 0.001) for one unit increase in genetically predicted log-transformed odds of type 2 diabetes. INTERPRETATION: This study based on genetic data suggests that a high body mass index and type 2 diabetes may be causal risk factors for kidney stone formation.