HIV-1 matrix protein p17 activates a variety of cell responses which play a critical role in viral replication and infection. Its activity depends on the expression of p17 receptors (p17R) on the surface of target cells. Whether p17 also plays a role in stimulating human monocytes, a major HIV-1 reservoir, is not known. Here we show that human monocytes constitutively express p17Rs and that p17 selectively triggers these cells to produce MCP-1. The effect of p17 on MCP-1 expression was observed at the transcriptional level and was primarily dependent on the activation of the transcription factor AP-1. p17 increased the binding activity of AP-1 complexes in a time- and dose-dependent manner. Deletion of the AP-1 binding sites in the MCP-1 promoter resulted in the lack of p17-induced MCP-1 transcription. In particular, the P3 binding site located between -69 and -63 position seems to be essential to MCP-1 mRNA induction in p17-treated monocytes. An ever increasing amount of evidences shows a tight link between biologically dysregulated monocytes, AP-1 activation, MCP-1 release and HIV-1 pathogenesis. Overall our results suggest that p17 may play a critical role in the monocyte-mediated inflammatory processes, which are suspected to be major precipitating events in AIDS-defining diseases.