Abstract: Stevens–Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, often including the ocular surface, and sometimes progresses to toxic epidermal necrolysis (TEN). SJS/TEN may be initiated by certain types of medication coupled with possible infection; however, few susceptibility genes have been identified as indicators for risk prediction, except for certain human leukocyte antigen alleles, although several candidate susceptibility genes were identified by candidate gene and genome-wide approaches. As an alternative genetic model, gene–gene interactions between candidate genes were investigated using high-dimensional variable selection methods such as iterative sure independence screening. Linkage disequilibria around the toll-like receptor (TLR)3 and prostaglandin E receptor (PTGER)3 genes were also investigated using additional single nucleotide polymorphisms in an extended additional sample set. A murine experimental allergic conjunctivitis (EAC) model was used to examine the functional interactions. Iterative sure independence screening analyses of Japanese SJS/TEN patients with ocular surface complications revealed 2 interactions that exerted SJS/TEN susceptibility effects, which were locus pairs of TLR3–PTGER3 and HLA-A–IL1α. Furthermore, functional interactions between TLR3 and EP3 (the protein of PTGER3) were demonstrated using the EAC model. Identification of functional interactions between TLR3 and EP3 supports an epistatic interaction conferring an increased risk for SJS with ocular complications.