The predisposition to stroke might involve interactive effects among variants in several genes. We tested this hypothesis by examining the influence of polymorphisms in methylenetetrahydrofolate reductase (MTHFR) (C677T) and prothrombin (F2) (G20210A) as risk factors for stroke in Morocco. The polymerase chain reaction-restriction fragment length polymorphism methods were used to analyze DNA from 91 stroke patients and 182 controls. Association between the two polymorphisms and the risk of stroke was estimated by four-level models for the analysis of genetic interaction. Neither the MTHFR 677TT nor the F2 20210GA genotype showed any significant association compared to the MTHFR CC and F2 GG genotypes, respectively. An interactive effect between the MTHFR 677TT and F2 20210GA polymorphisms showed an increased risk of stroke. The odds ratios, in univariate and multivariate analysis, for the combined polymorphisms were 4.99 (95% CI, 1.75-14.2, P = 0.001) and 5.29 (95% CI, 1.63-17.1, P = 0.005), respectively.