Angiogenesis is a multistep process that depends on the balance of proangiogenic factors and inhibitors as well as on interactions with the extracellular matrix. We examined the immunohistochemical expression of the defining angiogenic agents, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), and the antiangiogenic agent thrombospondin-1 (TSP-1) in 131 patients with urethelial carcinoma and correlated their expression levels with clinicopathological parameters. VEGF and MMP-9 expression was higher in high-grade tumors than in low-grade tumors (p = 0.000 and p = 0.001, respectively), whereas the reverse was true for TSP-1 (p = 0.000). VEGF and MMP-9 expression was higher in deeper tumors compared to superficial tumors and in invasive tumors compared to non-invasive tumors (p = 0.001 and p = 0.001, respectively), while TSP-1 was lower (p = 0.000). We could differentiate 22 of 41 muscle-invasive (T2) cases as superficial (T2a; n = 7) or deep (T2b; n = 15), but no difference was found between them regarding VEGF, MMP-9, or TSP-1 expression (p = 0.783, p = 0.289, and p = 0.783, respectively). There was a positive correlation between VEGF and MMP-9 expression (p = 0.008, r = 0.23) but a negative correlation between MMP-9 and TSP-1 expression (p = 0.014, r = -0.21). Increased VEGF and MMP-9 expression as well as decreased TSP-1 expression may play considerable roles in the invasion and differentiation of urothelial carcinoma. (C) 2009 Elsevier GmbH. All rights reserved.