LEDGFp75 is a cellular protein which binds human immunodeficiency virus type 1 (HIV-1) integrase with high specificity and affinity but whose function in infection has not been defined. We infected LEDGFp75-deficient primary macrophages with wild-type HIV in order to assess potential infection phenotypes which would provide clues to LEDGFp75 function. Silencing of LEDGFp75 by 70 to 80% resulted in an average of 53% reduced infection of macrophages by HIV. Analysis of infection intermediates showed that integration, but not two-long-terminal-repeat (2LTR) circles or late cDNAs, was reduced up to 74% in LEDGFp75-deficient macrophages. Therefore, LEDGFp75 has a modest involvement in HIV-1 integration in macrophages.