Matrix metalloproteinases (MMPs) secreted by human cytotrophoblasts are crucial for the invasion of the placental bed by these cells. The invasive growth of the trophoblast is similar to that of malignant tumours in many respects, but, unlike the latter, it is strictly controlled. Tissue inhibitors of metalloproteinases (TIMPs) have been postulated to play a role in the control of trophoblast invasion. In this immunohistochemical study, the distribution of TIMP-2 in the human placenta was investigated. In first trimester placenta, the cytotrophoblasts in columns exhibited strong cytoplasmic staining for TIMP-2. Villous cytotrophoblasts exhibited staining of moderate intensity with accentuation at the cell membrane, especially at the interfaces with the syncytiotrophoblast and the villous stroma. Staining of the cytoplasm and apical border of the syncytiotrophoblast was weak and focal. In term placenta, the few cytotrophoblasts present exhibited a staining pattern similar to that of the cytotrophoblasts in first trimester placenta, and there was marked linear staining of the syncytiotrophoblast at the interface with the stroma. Because it is the first trimester cytotrophoblast columns that invade the placental bed, the results demonstrate that the strongest immunoreactivity for TIMP-2 in the trophoblast is found in cells that are known to produce MMPs and exhibit an invasive growth pattern. These findings indicate that TIMP-2 may be involved in autoregulation of the invasive growth of the trophoblast.