Background: The aim was to investigate whether the effects of major risk factors for ischemic stroke were modified by long-term exposure to air pollution in Scania, southern Sweden. Methods: Cases were defined as first-ever ischemic strokes in patients born between 1923 and 1965 during 2001-2006 (n = 7,244). Data were collected from The Swedish National Stroke Register (Riks-stroke) and the Malmö and Lund Stroke Registers. Population controls were matched on age and sex. Modeled outdoor annual mean NO(x) concentrations were used as proxy for long-term exposure to air pollution. Heterogeneity across NO(x) categories was tested for smoking, hypertension, diabetes mellitus, atrial fibrillation and physical inactivity. Data were analyzed as case-control data and to some extent as case-only data, with logistic regression analysis. Results: The case-control odds ratios for ischemic stroke in association with diabetes were 1.3 [95% confidence interval (CI): 1.1-1.6] and 2.0 (95% CI: 1.2-3.4) in the lowest and highest NO(x) category, respectively (p value for testing heterogeneity across the categories = 0.056). The case-only approach gave further support for the risk associated with diabetes to increase with NO(x) (p for trend = 0.033). We observed no main effect of mean NO(x) or any conclusive effect modifications between NO(x) and smoking, hypertension, atrial fibrillation or physical inactivity. Conclusions: In a low-level air pollution area, the risk for ischemic stroke associated with diabetes seemed to increase with long-term exposure to air pollution.