Human leukocyte antigen DR2 (HLA-DR2), namely the allelic variant HLA-DR15, have been associated with lupus nephritis (LN) in Caucasians. The study investigated the relationships between HLA class II alleles and lupus nephritis in Italian patients. Two hundred forty-four patients fulfilling the American Rheumatism Association criteria for systemic lupus erythematosus (SLE) were typed for HLA-DRB1*, -DQA1*, -DQB1*, and -DPB1* alleles by polymerase chain reaction-sequence-specific oligonucleotide and polymears chain reaction-single-strand polymorphism; 71 patients had renal damage assessed by renal biopsy. Glomerulonephritis was classified using WHO criteria. Significance was tested by X(2) on 2x2 tables. HLA-DQA1*0101 was strongly associated with LN (OR = 2.72 [1.43-5.19]; p = 0.002), whereas HLA-DRB1*1501 was only marginally associated (OR = 1.94 [0.88-4.26]; p = not significant). HLA-DQA1*0102 demonstrated a significant protective effect (OR = 0.31 [0.14-0.86]; p = 0.002). On analyzing the distribution of HLA-DRB1*1501 bearing haplotypes in our SLE patients we found that the HLA-DRB1*1501 greatly enhanced the risk of developing LN conferred by the DQA1*0101 allele (OR = 65.96 [9.35-1326.25]), whereas DQA1*0102 suppressed the nephritogenic effect of DRB1*1501. At renal biopsy, 80% of DRB1*15 positive patients were classified as having class IV LN with the remaining 20% having class III LN. The figures were 19% and 21%, respectively, among the HLA-DR15 negative patients. In the Italian population HLA-DQA and HLA-DR alleles interact in conferring susceptibility to or protection against lupus nephritis, the diffuse proliferative glomerulonephritis (i.e., the most severe form of nephritis) is associated with the HLA-DR15 bearing haplotypes.