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To evaluate the presence of autonomic nervous system (ANS) involvement in HIV-positive drug users.We investigated 37 HIV-positive (and 18 HIV-negative controls) intravenous heroin users who were without symptoms and signs of autonomic or peripheral neuropathy.The patients were clinically and immunologically assessed and subjected to a battery of five cardiovascular reflex function tests.The tests revealed ANS involvement in 22 HIV-positive subjects but only in one HIV-negative subject. Immunoglobulin (Ig) G and C1q immune complex levels were significantly higher in HIV-positive subjects with severe cardiovascular reflex function tests alteration compared to those with normal tests. In a follow-up of 17 HIV-positive subjects, nine presented deteriorated reflexes in the tests and higher IgG immune complex levels.The results confirm that, by using sufficiently sensitive tests, signs of preclinical autonomic neuropathy can frequently be found in HIV-positive intravenous heroin users, as previously observed in homosexual patients, and suggest the existence of an HIV-related autoimmune pathogenesis. Early diagnosis of ANS involvement could be important, since the presence of autonomic dysfunction could increase the risk of cardiorespiratory arrest during invasive procedures.