Matrix metalloproteinases (MMPs) are calcium-dependent proteases that have the combined capacity to degrade all components of the extracellular matrix. Besides the degradation of extracellular matrix, which facilitates tissue remodeling and cell migration, their activity can result in the generation of epitopes that act as cell effectors or in the release of sequestered growth factors and cytokines. Free radicals, and the resulting oxidative stress, could affect the activity of MMPs both directly, through the oxidation of critical domains, and indirectly by modulating its expression through redox-sensitive elements such as NFkB and AP-1 that are known to be an integral part of the binding sites for MMP transcription. We and others have shown that heme is a potent pro-inflammatory molecule, able to induce the activation of human neutrophils and macrophages. Since heme is involved in the generation of oxidative stress by promoting reactive oxygen species (ROS) production we sought to investigate whether this molecule would be involved in the secretion and/or expression of MMPs in cultured macrophages. We first measured the ability of heme to induce superoxide production by using SOD-inhibitable cytochrome c reduction. RAW cells were stimulated with incresead concentrations of heme for 15 minutes, and the superoxide production was measured in the following 30 min. Our results indicated a clear dose-dependent induction of superoxide by heme. We then incubated these cells with heme and measured the activity of MMPs in the conditioned medium by zymography. We observed that heme induced the secretion of pro-MMP-2. This induction was blocked by pre-treating the cells with N-acetyl-cystein (NAC) and apocynin suggesting the potential involvement of ROS in this event. Later we examined whether the heme-induced MMP-2 expression was associated with translocation of NFkB to the nucleus. To do this, RAW cells were pre-treated with PDTC , an inhibitor of NFkB translocation and then stimulated with heme. Under this circunstance we observed the same effect of heme in inducing MMP-2 secretion, suggesting that NFkB is not involved in this phenomenon. Taken together, our results suggest that release of heme after hemolytic or hemorrhagic events can increase the secretion of MMPs, which could in turn, play an important role by promoting tissue/vascular remodeling.