OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Stills disease with atypical lung disease. We sought to characterise features of patients with Stills disease with DRESS compared with drug-tolerant Stills controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort. METHODS: In a case/control study, we collected a multicentre series of patients with Stills disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Stills controls (n=65). We retrospectively analysed clinical data from all Stills subjects and typed 94/131 for HLA. European Stills-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Stills cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Stills-DRESS cases (n=64) compared with drug-tolerant Stills controls (n=30). KD subjects (n=19) were similarly studied. RESULTS: Stills-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Stills-DRESS (64%) versus drug-tolerant Stills (3%; p=1.2×10-14). We found striking enrichment for HLA-DRB1*15 haplotypes in Stills-DRESS cases versus INCHARGE Stills controls (p=7.5×10-13) and versus self-identified, ancestry-matched Stills controls (p=6.3×10-10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions. CONCLUSIONS: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.