Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury with various origins. HLA-DQA1 , -DQB1 , and -DRB1 have been associated with development of tubulointerstitial nephritis and uveitis (TINU) syndrome in case reports and small case series, but information about HLA genetic susceptibility to drug hypersensitivity–related ATIN (D-ATIN) or other types of ATIN is limited. In this article, we genotyped 154 patients with ATIN of different causes and 200 healthy controls at HLA-DQA1 , -DQB1 , and - DRB1 loci. We found that there was no difference between patients with D-ATIN and TINU in the carrier’s frequency of HLA-DQA1 , -DQB1 , or -DRB1 . Patients with Sjogren’s syndrome–ATIN and IgG4-related ATIN presented a different pattern of tested HLA alleles. HLA-DQA1*0104 ( p value corrected by false discovery rate method [ Pc ] = 4.72 x 10 –22 , odds ratio [OR] = 13.81), -DQB1*0503 ( Pc = 1.95 x 10 –14 , OR = 9.51), and -DRB1*1405 ( Pc = 8.06 x 10 –19 , OR = 12.80) were significant risk alleles for the occurrence of D-ATIN and TINU. There were no significant associations between tested HLA alleles and ATIN induced by other causes. Patients with D-ATIN/TINU carrying HLA-DQA1*0104 / DQB1*0503 / DRB1*1405 had higher peak serum creatinine and more severe renal tubulointerstitial inflammatory impairment. They also had significantly higher levels of tubular HLA-DR and HLA-DQ expression, which were correlated with the numbers of interstitial CD4 + T lymphocytes ( r = 0.975, p 〈 0.001 and r = 0.832, p = 0.005, respectively) and monocytes/macrophages ( r = 0.721, p = 0.004 and r = 0.615, p = 0.02, respectively). In conclusion, patients with D-ATIN or TINU have genetic susceptibility in HLA - DQA1 , - DQB1 , and - DRB1 alleles. HLA-DQA1*0104/DQB1*0503/DRB1*1405 serves as a significant risk haplotype for development of D-ATIN and TINU, which might facilitate renal tubulointerstitial inflammation by enhancing Ag-presenting capacity of renal tubular cells.