Prostate-specific membrane antigen (PSMA), a type II transmembrane metallo-peptidase highly overexpressed in prostate cancer cells, has been studied as a targeting molecule in prostate cancer. Recently, PSMA has also been found to be expressed in the neovasculature of multiple nonprostatic solid tumors. Because of its unique expression pattern limited to tumor-associated endothelial cells, PSMA may also be an interesting molecule for vascular targeting. In this study, PSMA expression was determined by immunohistochemistry in 119 cases of primary gastric adenocarcinoma, 130 cases of primary colorectal adenocarcinoma, and 24 metastasis of colorectal adenocarcinoma. Expression data were correlated with clinicopathologic information. PSMA expression was detected in tumor-associated neovasculature of 79 (66%) of 119 gastric and 110 (85%) of 130 colorectal carcinomas. Furthermore, the neovasculatures of 16 (84%) of 19 liver and 4 (80%) of 5 nodal metastases from colorectal carcinomas were prostate-specific membrane antigen positive. There was a trend for high-grade tumors to higher PSMA expression (Spearman r = 0.18, P = .046) in colorectal cancers. No association between PSMA expression and overall- or disease-free survival was observed in gastric or colorectal cancers. This study provides the first in-depth look at PSMA expression in gastric and colorectal cancer. Because of its highly tumor-restricted expression and its accessibility to targeted therapy, PSMA represents a promising therapeutic and diagnostic target in colorectal and gastric cancer.