Freshly isolated blood monocytes show an early postentry block to in vitro HIV-1 infection. Differentiation into monocyte-derived macrophages (MDMs) is required to allow HIV replication in this cell type. In this study, we investigated whether the resistance of monocyte to HIV infection stemmed from uncoating defect. Monocyte and MDM lysates induced HIV-1 core uncoating to a comparable degree. This suggests that monocyte lacks a factor(s) essential for viral reverse transcription and/or contains a factor(s) interfering with this step.