Detecting gene-gene interactions in single-nucleotide polymorphism data is vital for understanding disease susceptibility. However, existing approaches may be limited by the sample size in case-control studies. Herein, we propose a balance approach for the multifactor dimensionality reduction (BMDR) method to increase the accuracy of estimates of the prediction error rate in small samples. BMDR explicitly selects the best model by evaluating the average of prediction error rates over k-fold cross-validation without cross-validation consistency selection. In this study, we used several epistatic models with and without marginal effects under different parameter settings (heritability and minor allele frequencies) to evaluate the performance of existing approaches. Using simulated data sets, BMDR successfully detected gene-gene interactions, particularly for data sets with small sample sizes. A large data set was obtained from the Wellcome Trust Case Control Consortium, and results indicated that BMDR could effectively detect significant gene-gene interactions.