SummaryAspirin‐exacerbated respiratory disease (AERD) is prevalent in about 10% of asthma patients and is characterized by a severe decline in forced expiratory volume in 1‐s (FEV1), an important phenotype for total lung capacity, upon ingestion of aspirin. The general transcription factor IIH subunit 4 (GTF2H4) is positioned at 6p21.33, a part of the major histocompatibility complex (MHC) class II region that contains a number of genes that play an important role in the immune system. In addition, genetic variants in another general transcription factor IIH gene have revealed significant association with lung disease. To investigate whether GTF2H4 genetic variants could be a causative factor for AERD development and FEV1 decline by aspirin provocation, five common single‐nucleotide polymorphisms (SNPs) were genotyped in 93 patients with AERD and 96 aspirin‐tolerant asthma (ATA) controls. As a result, when adjusted for age, gender, smoking status and atopy as covariates, the rs1264307 variant and two haplotypes showed nominal signals in the association with AERD (P = 0.02–0.04), but the significances disappeared after corrections for multiple testing (corrected P > 0.05). In further multiple regression analysis, no genetic variants of GTF2H4 showed significant associations with FEV1 decline by aspirin provocation in asthmatics (P > 0.05). Despite the need for replications in larger cohorts, our preliminary findings suggest that GTF2H4 variants may not be associated with susceptibility to AERD and obstructive symptoms in asthmatics.