Colorectal cancer (CRC) is the third leading cause of cancer deaths with an estimated 57,000 deaths per year in the United States. Evidence for a role of estrogens in colon cancer is accumulating, although the mechanism through which this is mediated is not clear. Epidemiological studies suggest that post-menopausal hormone replacement therapy (HRT) reduces CRC incidence. There is also evidence to suggest populations that consume soy and soy foods have reduced colon cancer risk. Soy contains phytoestrogens, such as the isoflavone genistein, that are similar to endogenous estrogens. Several studies have suggested isoflavones may have potential anticarcinogenic effects. In previous work, our group found a reduced colon tumor incidence in carcinogen-treated mice fed diets containing estrone (E1). Moreover, several epidemiological studies indicate a 40-50% reduction in the risk of developing colorectal cancer with chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. It is suggested that NSAIDs provide anticancer activity by inhibiting both isoforms of the cyclooxygenase (COX) enzymes COX-1 and COX-2. Increased COX-2 activity is an early event in CRC. With emerging evidence indicating suppression of COX by estrogens we hypothesized that dietary genistein or estrone (E1) would reduce aberrant crypt foci (ACF), purported preneoplastic markers of colon carcinogenesis, and cyclooxygenase-2 (COX-2) protein levels. Ovariectomized female mice were fed diets containing casein (Casein), soy protein without isoflavones (Soy-IF), soy protein with genistein (Soy+Gen) or soy protein with estrone (Soy+E1) from 3 weeks of age. Starting at 4 weeks of age, all animals were administered weekly injections of azoxymethane (AOM) 10 mg/kg of body weight for 6 weeks, and then terminated 6 weeks after the last dose of AOM. Colons sections stained with methylene blue were visualized under a light microscope for ACF, and COX-2 protein levels were analyzed by Western Immunoblot. A significant effect of diet on COX-2 protein levels but not ACF was observed. COX-2 protein levels were lower in mice fed Soy+E1 and Soy+Gen compared with mice fed Casein or Soy-IF. Thus, we conclude that soy protein with genistein and soy protein with estrone down regulated COX-2 levels in mouse colon suggesting a potential role in reducing colon cancer risk.