HLA Class I soluble antigen serum levels have been evaluated in 178 subjects who were positive for human immunodeficiency virus (HIV) and in 66 HIV-negative controls. The serum levels of HIV p24 antigen, interleukin 2 receptor (IL 2r), CD8 soluble antigen (CD 8ag), B2-microglobulin (B2-m), and neopterin (Npt), as well as the number of CD4+ and CD8+ T cells were also evaluated. Results show that mean HLA class I serum levels of HIV-positive subjects: (1) are significantly higher than controls (p less than 0.001); (2) increase with disease progression (67.7 RU/ml, 103.4 RU/ml, and 169.6 RU/ml for subjects belonging to groups II, II, and IV of the Centers for Disease Control [CDC] classification, respectively); (3) correlate with HIV p24 antigen, IL2r, and CD 8 soluble antigen levels. Present data show that elevated levels of HLA class I soluble antigens, correlating with disease stage, are found in sera of HIV-positive subjects. Circulating HLA class I molecules, interfering with some immune functions, might contribute to the pathogenesis of the immune deficiency of HIV-positive subjects.