Purpose <p>The anticancer drug regorafenib can induce erythema multiforme (EM), an immune-mediated cutaneous and mucosal hypersensitivity reaction. We prospectively analyzed regorafenib in patients with metastatic colorectal cancer (mCRC) and found that seven of 40 patients had grade 3 EM, which resulted in treatment discontinuation. In this study, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe EM.</p> Methods <p>To identify associated polymorphisms, exploratory whole-exome sequencing was performed focusing on factors related to type IV hypersensitivity reaction in seven patients each, with and without grade 3 EM. The identified EM-related polymorphisms were analyzed in all 40 patients. Class II human leukocyte antigen (<i>HLA</i>) typing was also performed for all patients.</p> Results <p>The frequency of interleukin 12 receptor (<i>IL12R</i>)<i>B2</i> rs2229546 A/A was higher in patients with grade 3 EM than in those without it (<i>P</i> = 0.00622, <i>Pc</i> = 0.0622 [Bonferroni corrections]). Polymorphisms of the retinoic acid receptor-related orphan receptor (<i>ROR</i>)<i>C</i>, rs2280471 G, rs12145375 T, rs12144914 G, and rs55841824 T comprised haplotype I. The frequency of patients homozygous or heterozygous for haplotype I was lower in those with grade 3 EM than in those without EM (<i>P</i> = 0.0108, <i>Pc</i> = 0.108). The combination of the risk genotype of <i>IL12RB2</i> rs2229546 A/A and the risk diplotype that did not contain <i>RORC</i> haplotype I was significantly associated with a higher incidence of grade 3 EM (<i>P</i> = 0.000383, <i>Pc</i> = 0.00153). The class II <i>HLA</i> haplotypes were not associated with EM.</p> Conclusions <p>Type IV hypersensitivity reaction-related polymorphisms were associated with regorafenib-induced EM.</p> Trial registration number and date <p>UMIN000013939, registered on May 12, 2014, when six months after approval by the Institutional Review Board of Showa Medical University.</p>