Objective: The purpose of this study was to investigate the differential expression of angiopoietin-1, angiopoietin-2, and Tie receptors (Tie-1 and Tie-2) in placentas from pregnancies complicated by placenta accreta., Study Design: Paraffin sections of 46 placental specimens with (cases) and 46 without (controls) placenta accreta were studied immunohistochemically for the expression of Tie receptors and angiopoietin-2 in trophoblast populations. Protein levels of Tie receptors and angiopoietins were also examined by Western blot analysis and/or enzyme-linked immunosorbent assay. Controls were matched for gestational age in this case-control study., Results: In both second and third trimesters, the percentage of intermediate/strong immunoreactivity of Tie-2 in the syncytiotrophoblast was significantly lower in cases than controls (P = .015 and .025, respectively). However, Tie-2 expression in the cytotrophoblastic and extravillous trophoblastic cells and Tie-1 in all trophoblast subpopulations were not significantly different between cases and controls (P > .05). The majority of Tie-2 expression, as demonstrated by Western blots, was consistent with the trends of immunohistochemical findings in the syncytiotrophoblast. Enzyme-linked immunosorbent assay in the placental lysates showed that women with placenta accreta demonstrated significantly higher angiopoietin-2 and lower Tie-2 concentrations than did women with normal pregnancies (P = .026 and .003, respectively). Placental angiopoietin-1 levels did not have any significance (P > .05). Also, angiopoietin-2 immunoreactivity in the syncytiotrophoblast was compatible with the finding demonstrated by enzyme-linked immunosorbent assay (P = .005 and .012, respectively)., Conclusion: These observations suggest that the participation of up-regulated angiopoietin-2 and down-regulated Tie-2 in the placental tissues may indicate a role for these angiogenic factors in the development of placenta accreta.