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Objective Gallstone carriers have elevated cardiovascular disease (CVD) risk. Shared lifestyle risk factors only partly explain the observed association. Gallstone-driven inflammation may contribute to CVD with cholecystectomy offering protection. A triangulation study using observational, genetic and interventional data was undertaken.Design Cox proportional hazards analysis of UK Biobank data assessed 10-year CVD risk in gallstone cases versus healthy controls and gallstone carriers versus post-cholecystectomy individuals. Data were meta-analysed with other published cohorts. Gallstone state was additionally modelled as a time-varying covariate with states: gallstone-free, gallstone-carrier, gallstone-related inflammation and post cholecystectomy. Finally, Mendelian randomisation (MR) analyses were undertaken using 41 gallstone-promoting single nucleotide polymorphisms (SNPs) to assess causal effects of gallstones on CVD.Results In UK Biobank (gallstones=32,528, controls=424,520) and meta-analysis (gallstones=202,055, controls=1,256,861), gallstones were associated with CVD (adjusted HR (aHR) 1·28 (1·20 to 1·36), meta-analysis aHR 1·23 (1·18 to 1·29)). Cholecystectomy was associated with reduced CVD risk compared with gallstone carriers (aHR 0·71 (0·62 to 0·82)). Time-varying analysis supported elevated CVD risk with inflammation and reduced CVD following cholecystectomy. MR analyses required handling of pleiotropic cholesterol-lowering SNPs that affect CVD risk independently of gallstones. Multivariable MR adjusting for the impact of SNPs on lipids showed no significant association of CVD and gallstones.Conclusion Gallstones are associated with elevated CVD risk, which increased with gallstone-related inflammation but diminished post cholecystectomy. The benefits of cholecystectomy indicate a potential causal pathway. However, as cholecystectomy interrupts exposure to gallstones, the effects of gallstone-promoting SNPs on CVD are likely attenuated by cholecystectomy, meaning MR analyses cannot detect an underlying causal effect.