Background: Bladder cancer (BCa) is a heterogeneous disease with a variable prognosis and natural history. Cardiovascular disease (CVD), although completely different, has several similarities and possible interactions with cancer. The association between them is still unknown, but common risk factors between the two suggest a shared biology. Materials and Methods: This was a retrospective study that included patients who underwent transurethral resection of bladder tumor at two high-volume institutions. Depending on the presence of a previous history of CVD or not, patients were divided into two groups. Results: A total of 2050 patients were included, and 1638 (81.3%) were diagnosed with bladder cancer. Regarding comorbidities, the most common were hypertension (59.9%), cardiovascular disease (23.4%) and diabetes (22.4%). At univariate analysis, independent risk factors for bladder cancer were age and male sex, while protective factors were cessation of smoking and presence of CVD. All these results, except for ex-smoker status, were confirmed at the multivariate analysis. Another analysis was performed for patients with high-risk bladder cancer and, in this case, the role of CVD was not statistically significant. Conclusions: Our study pointed out a positive association between CVD and BCa incidence; CVD was an independent protective factor for BCa. This effect was not confirmed for high-risk tumors. Several biological and genomics mechanisms clearly contribute to the onset of both diseases, suggesting a possible shared disease pathway and highlighting the complex interplay of cancer and CVD. CVD treatment can involve different drugs with a possible effect on cancer incidence, but, to date, findings are still inconclusive.