Background and Purpose Risk factors for stroke recurrence have usually been evaluated as single variables. This study is a multivariate analysis of five risk factors (hypertension, myocardial infarction, cardiac arrhythmia, diabetes mellitus, and transient ischemic attacks) for second stroke after an initial ischemic stroke. Methods Six hundred twenty-one patients with an acute ischemic stroke were followed prospectively first at 4 months after onset and then at approximately 6-month intervals until death, recurrence of stroke, or the end of the study. The five risk factors were measured at each visit. A Cox multifactorial regression analysis was conducted using the risk factor status at enrollment and adjusted for age and sex. Results Follow-up averaged 24 months (range, 1 to 48 months). Men comprised 52% of the cohort and were slightly older; 97% of the cohort was white, and 57% had multiple risk factors. Hypertension occurred in 59%, cardiac arrhythmia in 47% (of which 16% had atrial fibrillation), diabetes mellitus in 30%, myocardial infarction in 25%, and transient ischemic attacks in 18%. Only history of hypertension and atrial fibrillation by electrocardiogram were associated with increased risk of second stroke independently and significantly (P=.01 and P=.04, respectively). Conclusions Among the five factors analyzed, control of hypertension and atrial fibrillation appear to offer the greatest chance of reducing risk of stroke recurrence after an ischemic stroke.