Few studies have investigated the pathophysiologic mechanisms responsible for what seems to be a possible interaction between Plasmodium falciparum, the causative agent of malaria, and HIV-1 in dually infected patients. It has been shown that Plasmodium parasites detoxify heme molecules into a pigment called hemozoin (HZ), which can significantly modulate the immune system. The primary objective of this study was to determine whether exposure of human primary monocyte-derived macrophages (MDMs) to the malaria pigment influences the process of HIV-1 infection. We report here that HIV-1 replication is significantly diminished in HZ-loaded MDMs. The HZ-mediated reduction in virus replication is due to a block at a step in the virus life cycle occurring between the completion of full-length reverse transcripts and integration of viral DNA within the host chromosome. Understanding the pathological mechanisms involved in P. falciparum and HIV-1 co-infection is of high importance because of possible therapeutic ramifications.