Stroke is the leading cause of disability worldwide. It is known that atrial fibrillation and left atrial enlargement contribute ischemic stroke, and mean platelet volume (MPV) increases in patients with ischemic stroke and atrial fibrillation. We aimed to determine whether higher MPV is associated with ischemic stroke in patients with sinus rhythm. We evaluated 74 patients in sinus rhythm and with ischemic stroke (Group 1) and 90 age-matched and sex-matched healthy individuals as control group (Group 2). After physical and echocardiographic examination, 24–48 h Holter monitoring and complete blood counts were studied. There were no statistically significant differences in age, sex rates, and comorbidities between groups. Left atrial diameter was higher in Group 1 than Group 2 (P = 0.001), but both were in normal range. MPV was significantly higher in Group 1 (P < 0.001) and was an independent determinant [odds ratio (OR): 1.840; P < 0.001; 95% confidence interval (CI) 1.330–2.545] of ischemic stroke with left atrial (OR: 1.138; P = 0.006; 95% CI 1.037–1.248). In conclusion, higher MPV is associated with acute ischemic stroke in patients with sinus rhythm and without heart failure or left atrial enlargement. MPV and left atrial diameter are independent predictors of ischemic stroke in this patient population.