Abstract Background: Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNP) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP–SNP interactions from genes involved in several different immune-related pathways for investigation in future studies. Methods: The study population consisted of two case groups: 1,224 histologic confirmed, non-Hispanic white glioma cases from the United States and a validation population of 634 glioma cases from the United Kingdom. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the ORs of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes. Results: Using this data mining strategy, we found 396 significant SNP–SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations. Conclusion: This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case–control study designs to obtain estimates of risk. Impact: This is the first study, to our knowledge, to take this novel approach to identifying SNP–SNP interactions relevant to glioma etiology. Cancer Epidemiol Biomarkers Prev; 20(8); 1683–9. ©2011 AACR.