We aimed at identifying transcripts whose expression is regulated by a SNP-SNP interaction. Out of 47,294 expression phenotypes we used 3107 transcripts that survived an extensive quality control and 86,613 linkage disequilibrium-pruned SNP markers that have been genotyped in 210 individuals. For each transcript we defined cis-SNPs, tested them for epistasis with all trans-SNPs, and corrected all observed cis-trans-regulated expression effects for multiple testing. We determined that the expression of about 15% of all included transcripts is regulated by a significant two-locus interaction, which is more than expected (P = 2.86 × 10(-144)). Our findings suggest further that cis-markers with so called 'marginal effects' are more likely to be involved in two-locus gene regulation than expected (P = 8.27 × 10(-05)), although the majority of interacting cis-markers showed no one-locus regulation. Furthermore, we found evidence that gene-mediated trans-effects are not a major source of epistasis, as no enrichment of genes has been found in close vicinity of trans-SNPs. In addition, our data support the notion that neither chromosomal regions nor cellular processes are enriched in epistatic interactions. Finally, some of the cis-trans regulated genes have been found in genome-wide association studies, which might be interesting for follow-up studies of the corresponding disorders. In summary, our results provide novel insights into the complex genome-transcriptome regulation.