Co‐trimoxazole (CTX) causes various forms of severe cutaneous adverse reactions (SCARs). This case‐control study was conducted to investigate the involvement between genetic variants of human leukocyte antigen (HLA) and CYP2C9 in CTX‐induced SCARs, including Stevens‐Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in Thai patients. Thirty cases of CTX‐induced SCARs were enrolled and compared with 91 CTX‐tolerant controls and 150 people from the general Thai population. Cases comprised 18 SJS/TEN and 12 DRESS patients. This study demonstrated that genetic association of CTX‐induced SCARs was phenotype‐specific. HLA‐B*15:02 and HLA‐C*08:01 alleles were significantly associated with CTX‐induced SJS/TEN, whereas the HLA‐B*13:01 allele was significantly associated with CTX‐induced DRESS. In addition, a significant higher frequency of HLA‐A*11:01‐B*15:02 and HLA‐B*13:01‐C*03:04 haplotypes were detected in the group of CTX‐induced Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and DRESS cases, respectively. Genetic association of CTX‐induced SCARs is phenotype‐specific. Interestingly, these association was observed only in HIV‐infected patients but not in non‐HIV‐infected patients.