The present cross-sectional study evaluated the status and relationship of interleukin-6, a platelet growth factor, with platelet counts, viral load, CD4 counts, and antiretroviral treatment in 75 HIV-infected subjects with thrombocytopenia and 50 gender-, race-, age- and antiretroviral treatment-matched controls without thrombocytopenia. Mean IL-6 production was significantly higher in thrombocytopenic participants (13 432+/-8596) than in non-thrombocytopenic subjects (12 859+/-3538 pg/10(5) Lym). Univariate analyses indicated, however, that thrombocytopenic patients were more likely to have <3000 pg of IL-6 than non-thrombocytopenic patients (OR=7 95% CI 1.3-12; P=0.01). For additional analyses, participants were dichotomized above and below 3000 pg of IL-6. Despite similar age, gender, drug use and antiretroviral treatment, thrombocytopenic participants had lower CD4 counts (186.5+/-149 vs. 401+/-286, P=0.005) than non-thrombocytopenic subjects. Thrombocytopenic participants with elevated IL-6, with or without HAART, were more likely to have higher HIV-replication (496 273+/-210 416; 34 656+/-25 332) than thrombocytopenic individuals with low IL-6 levels (105 332+/-42 699; 19 015+/-14 296 P=0.05). Non-thrombocytopenic patients with high IL-6 levels exhibited the highest CD4s (466.7+/-333) and the lowest viral burden (63 094+/-53 300) of the groups. Two distinct categories of HIV-associated thrombocytopenia exist: one accompanied by low IL-6, and another with compensatory elevations of IL-6. In thrombocytopenic individuals, the latter was associated with the poorest immunological and virological responses.