Background: Epidemiological studies have shown a close association between osteoarthritis (OA) and cardiovascular disease (CVD), but reliable evidence needs to be provided. We performed a two-sample Mendelian randomization (MR) study to examine the potential causal effect between OA and CVD.Methods: Exposures were self-reported OA, knee osteoarthritis (KOA), and hip osteoarthritis (HOA). The outcomes were 12 CVDs, including heart failure, atrial fibrillation, coronary artery disease, pulmonary embolism, stroke and its subtypes, myocardial infarction, coronary heart disease, and primary hypertension. All outcomes were obtained from published genome-wide association studies. The inverse-variance weighted method was used as the primary MR analysis. Heterogeneity tests and sensitivity analyses were conducted to validate the accuracy of the MR results.Results: Self-reported OA increased the incidence of small vessel stroke (odds ratio [OR] = 1.25, 95% confidence interval [CI]: 1.02-1.52, p = 0.03) and primary hypertension (1.01 [1.00-1.02], p < 0.01). HOA increased the incidence of stroke (1.06 [1.01-1.11], p = 0.02) and two subtypes (cardioembolic stroke: 1.12 [1.02-1.23], p = 0.02; ischemic stroke: 1.06 [1.01-1.11], p = 0.03). Patients with KOA had an increased risk of heart failure (1.10 [1.04-1.16], p < 0.01), atrial fibrillation (1.08 [1.02-1.13], p < 0.01), small vessel stroke (1.21 [1.06-1.39], p = 0.01), and primary hypertension (1.01 [1.01-1.02], p < 0.01).Conclusions: Patients with OA have an increased risk of several CVDs. The causality of this relationship may have clinical implications for improving the quality of prevention and treatment.