The relationship between Epstein-Barr virus (EBV) viral load in peripheral blood and HIV infection was determined in 103 HIV-infected patients. Epstein-Barr virus was detected by polymerase chain reaction in 75% of the patients, 21% of whom had the more uncommon EBV subtype 2. The highest levels of EBV were found in patients with 100-400 CD4+ cells/mm3 and not in those with more profound immunosuppression. An association was identified between EBV load and HIV proviral levels (p < 0.001), an IgM response to EBV early antigens (p < or = 0.01) and p24 antigenemia (p < 0.01 in patients with > 100 CD4+ cells), but not with other clinical or laboratory parameters. Combinations of different EBV and HIV parameters identified a subgroup of patients with a 2.2- to 4.8-fold risk of > or = 35% decline in CD4+ counts over six months. The association between EBV and HIV markers may reflect a significant pathogenic interaction between the two viruses.