To investigate the relationship between HLA class II genotypes and toxic intolerance during treatment with Tiopronin, a slow-acting drug used in the treatment of rheumatoid arthritis (RA), we studied 40 patients who were divided into two groups: a group of 22 patients without side effects and a group of 18 patients with intolerance to Tiopronin. The PCR-RFLP method was used to determine the HLA-DR, DQ and DP genotypes. The patients in the two groups had similar genetic backgrounds with an expected high frequency of DRI and DR4 alleles. However, DR1/DR4 heterozygosity was significantly increased in patients with intolerance (p = 0.03, Odds Ratio = 10.5). In addition, one intolerant patient had a DR1/DR7 genotype which shared DRw53 (DRB4*0101) with DR1/DR4. Furthermore, two subtypes of DR5, DRB1*1102 and DRB1*1201, were increased among intolerant patients (11.1% vs 0%, p = 0.03, OR = 13.97). In total, DR1/DRw53 heterozygotes, DRB1*1102 and DRB1*1201 represented 61.1% of intolerant patients. Therefore, a detailed HLA class II typing might be useful before RA treatment by Tiopronin to predict and avoid toxic side effects in the patients with increased risk. Further investigation is currently underway.