BACKGROUND: There is controversy surrounding the risk of ischemic stroke associated with the use of calcium supplements either in monotherapy or in combination with vitamin D. METHODS AND RESULTS: A nested case-control study was performed with patients aged 40 to 89 years old, among whom a total of 2690 patients had a first episode of nonfatal ischemic stroke and for which 19 538 controls were randomly selected from the source population and frequency-matched with cases for age, sex, and calendar year. Logistic regression provided the odds ratios while adjusting for confounding factors. A sensitivity analysis was performed by restricting to patients who were new users of calcium supplements as either monotherapy or with vitamin D. Calcium supplementation with vitamin D was not associated with an increased risk of ischemic stroke (odds ratio 0.85; 95% confidence interval, 0.67-1.08) in the population as a whole or under any of the conditions examined (dose, duration, background cardiovascular risk, sex, or age). Calcium supplement monotherapy was not associated with an increased risk in the population as a whole (odds ratio 1.18; 95% confidence interval, 0.86-1.61), although a significant increased risk at high doses (≥1000 mg/day: odds ratio 2.09; 95% confidence interval, 1.25-3.49; <1000 mg: odds ratio 0.76; 95% confidence interval, 0.45-1.26) compared with nonuse was observed. The sensitivity analysis did not affect the inferences, with similar results observed among new users as to the overall study population. CONCLUSIONS: This study suggests that calcium supplements given as monotherapy at high doses may increase the risk of ischemic stroke, whereas their combination with vitamin D seems to offset this hazard.