BACKGROUND The cyclooxygenase (COX) enzyme catalyzes the formation of prostaglandins, which can affect cell proliferation and alter the response of the immune system to malignant cells. The inducible form of COX, COX‐2, has been shown to be important in carcinogenesis. METHODS The authors studied COX‐1 and ‐2 expression in 20 tumors of the lung, colon, and breast (60 total) by using commercially available monoclonal and polyclonal antibodies on formalin fixed, paraffin embedded tissue. Our evaluation also included seven carcinoma‐associated colonic adenomas and 10 mammary ductal carcinomas in situ (DCIS). Quantitation of immunoreactivity was accomplished using an immunohistochemical scoring system that approximates the use of image analysis‐based systems. RESULTS Ninety percent of lung tumors (squamous cell carcinomas and adenocarcinomas), 71% of colon adenocarcinomas and 56% of breast tumors (DCIS and infiltrating ductal and lobular carcinomas) expressed COX‐2 at a moderate to strong level, which was significantly different from the negligible expression in distant nonneoplastic epithelium (controls; P < 0.0001). Poorly differentiated histologic features were correlated with low COX‐2 expression overall, especially in colon carcinomas. Among breast carcinomas, DCIS was more likely to express COX‐2 than invasive carcinomas. Adenomatous colonic epithelium showed moderate COX‐2 expression, as did adjacent nonneoplastic epithelium. COX‐1 immunoreactivity was essentially weak to moderate in all tissues evaluated. CONCLUSIONS COX‐2 expression is upregulated in well and moderately differentiated carcinomas of the lung, colon, and breast whereas COX‐1 appears to be constitutively expressed at low levels. A possible COX‐2 paracrine effect is suggested by moderate immunoreactivity in adjacent nonneoplastic epithelium. Cancer 2000;89:2637–45. © 2000 American Cancer Society. The inducible form of the cyclooxygenase (COX) enzyme, COX‐2, has been shown to be important in carcinogenesis. In this study, immunohistochemistry was used to document significant overexpression of COX‐2 in common human cancers and their precursors. Collectively, these data suggest that COX‐2 inhibitors may be utilized to prevent and treat neoplasms of the lung, colon, and breast.