The relationship between vitamin D deficiency and stroke was cross-sectionally evaluated in the high-risk Asian Indian population. Age- and gender-matched, 239 ischemic stroke patients and 241 control subjects were recruited. Vitamin D status was estimated by measuring serum 25-hydroxyvitamin D (25(OH)D) levels. After multivariate adjustment for a range of potential covariates in a logistic regression model, an inverse association was found between serum 25(OH)D concentration and risk of ischemic stroke: subjects with severely low 25(OH)D levels (⩽9.33 ng ml(-1)) were found to be at 3.13-fold (95% confidence interval (CI), (1.22-8.07)) increased risk of ischemic stroke as compared with those with high levels. Adjustment for systolic blood pressure levels was found to abrogate this association (odds ratio (OR)=2.00, 95% CI=0.61-6.50). On stratification, a pronounced association was found between low 25(OH)D and risk of ischemic stroke in hypertensives, OR=13.54, 95% CI=1.94-94.43 as compared with no association in non-hypertensives, (Pinteraction=0.04). We conclude that high blood pressure partly explains the association between 25(OH)D levels and ischemic stroke. Presence of hypertension amply aggravates the risk of ischemic stroke associated with low vitamin D levels. Meticulous management of hypertension, regular monitoring of serum 25(OH)D levels and treatment of severe vitamin D deficiency, particularly in hypertensive subjects, could help in effective prevention of stroke.