Complement activation by HIV results in the binding of C3 fragments to the gp160 complex and enhanced infection of C3 receptor‐bearing target cells. We have studied complement‐mediated enhancement of infection of the human CD4‐positive T‐cell line HPB‐ALL which expresses the CR1 (CD35) and CR2 (CD21) receptors for C3. CR1 and CR2 are present on 15% and 40% of normal peripheral blood CD4‐positive T lymphocytes respectively. Opsonization of the virus with complement resulted in a 3‐ to 10‐fold enhancement of infection of HPB‐ALL cells, as assessed by measuring the release of p24 antigen in culture supernatants throughout the culture period. Blockade of CR2 with cross‐linked anti‐CR2 monoclonal antibodies decreased infection to the level observed with unopsonized virus. Blocking CR1 reduced complement‐mediated infection by 50–80%. Experiments using serum deficient in complement factor I demonstrated that CR1 mediates the interaction between opsonized virus and T cells in addition to its ability to serve as a cofactor for the cleavage of C3b into smaller fragments that interact with CR2. A requirement for CD4 in complement‐mediated enhancement of infection was observed with HIV‐1 Bru but not with HIV‐1 RF. Thus, CR1 and CR2 contribute in an independent and complementary fashion to penetration of opsonized virus into complement receptor‐expressing T cells. Involvement of CD4 in infection with opsonized virus depends on the viral strain.