<b><i>Background:</i></b> Subclinical cancer can manifest as a thromboembolic event and may be detected at a later interval in ischemic stroke survivors. We determined the rate of incident cancer and effect on cardiovascular endpoints in a large cohort of ischemic stroke survivors. <b><i>Methods:</i></b> An analysis of 3,680 adults with nondisabling cerebral infarction who were followed for two years within the randomized, double-blinded VISP trial was performed. The primary intervention was best medical/surgical management plus a daily supplementation of vitamin B6, vitamin B12, and folic acid. We calculated age-adjusted rates of incidence of cancer among ischemic stroke survivors and standardized incidence ratios (SIR) with 95% confidence intervals (CI) based on comparison with age-adjusted rates in the general population. The significant variables from univariate analysis were entered in a Cox Proportional Hazards analysis to identify the association between various baseline factors and incident cancer after adjusting age, gender, and race/ethnicity. A logistic regression analysis evaluated the association between incident cancer and various endpoints including stroke, coronary heart disease, myocardial infarction, and death after adjusting age, gender, and race/ethnicity. <b><i>Results:</i></b> A total of 3,247 patients (mean age ± SD of 66 ± 11; 2,013 were men) were cancer free at the time of enrollment. The incidence of new cancer was 0.15, 0.80, 1.2, and 2.0 per 100 patients at 1 month, 6 months, 1 year, and 2 years, respectively. The age-adjusted annual rate of cancer in patients with ischemic stroke was higher than in persons in the general population at 1 year (581.8/100,000 persons vs. 486.5/100,000 persons, SIR 1.2, 95% CI 1.16-1.24) and 2 years (1,301.7/100,000 vs. 911.5/100,000, SIR 1.4, 95% CI 1.2-1.6) after recruitment. There was a higher risk for death (odds ratio (OR) 3.1, 95% CI 1.8-5.4), and composite endpoint of stroke, coronary heart disease, and/or death (OR 1.4, 95% CI 1.0-2.2) among participants who developed incident cancer compared with those who were cancer free after adjusting for potential confounders. <b><i>Conclusions:</i></b> The annual rate of age-adjusted cancer incidence was higher among ischemic stroke patients compared with those in the general population. The odds of mortality were three folds higher among stroke survivors who developed incident cancer.