Intrabiliary growth by metastatic colorectal carcinoma (CRC) is an unusual finding that can clinically mimic cholangiocarcinoma. We evaluated prevalence of intrabiliary growth by retrospective review of 1596 diagnostic reports and by prospective evaluation of 223 hepatectomies. Positive cases were scored for extent of intrabiliary growth (major vs. minor duct involvement), architectural pattern (colonization of biliary epithelium and/or intrabiliary tumor plugs), and secondary sclerosing cholangitis in non-neoplastic parenchyma. By retrospective review, we identified intrabiliary growth in 41 (3.6%) of 1144 metastatic CRCs but only 3 (0.7%) of 452 noncolorectal tumors (P<0.001). Prospectively, we found intrabiliary growth in 18 (10.6%) of 170 metastatic CRCs and 1 (1.9%) of 53 other tumors (P=0.05). Among our final population of 43 CRCs with intrabiliary growth, 24 (56%) had major and 19 (44%) had minor duct involvement, 35 (81%) showed colonization of biliary epithelium, and 35 (81%) showed intrabiliary tumor plugs. Compared with minor duct involvement and 51 controls without intrabiliary growth, major duct involvement was more likely to produce obstructive liver chemistries (P=0.004), radiographic evidence of biliary disease (P<0.0001), and sclerosing cholangitis in non-neoplastic liver (P<0.0001). However, there was no impact on overall survival. Clinically, 5 (21%) cases of major duct involvement resulted in diagnostic uncertainty between metastatic CRC and cholangiocarcinoma. These findings underscore the frequency of intrabiliary growth by metastatic CRCs and its rarity with other metastases. Major duct involvement should be recognized because of its distinctive clinical features, which can overlap with cholangiocarcinoma.