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Soluble CD8 levels in sera were quantitated in asymptomatic intravenous drug abusers, homosexuals, and patients with lymphadenopathy or acquired immunodeficiency syndrome. Soluble CD8 levels were elevated in human immunodeficiency virus-seronegative intravenous drug abusers and homosexuals, probably reflecting infections like cytomegalovirus. The sera of human immunodeficiency virus-seropositive groups of patients with human immunodeficiency virus infection also had elevated levels of soluble CD8, reflecting infections like cytomegalovirus and human immunodeficiency virus infection.