We describe 8 cases of cholecystectomy specimens (6 laparoscopic and 2 open cholecystectomies) with Rokitansky-Aschoff (R-A) sinuses that were misinterpreted as adenocarcinomas. They were compared with 8 examples of classical R-A sinuses and 6 cases of R-A sinuses containing foci of adenocarcinoma. Five cases misinterpreted as adenocarcinomas consisted of densely packed, closely opposed R-A sinuses with little intervening stroma or surrounded by a desmoplastic stroma. They were lined by a single layer of cuboidal or columnar cells. There were also pseudostratified columnar cells with mucin-containing cytoplasm and hyperchromatic or vesicular nuclei but without mitotic figures. In 2 cases, the columnar cells had subnuclear vacuoles. Small papillary projections into R-A sinuses were seen in 4 cases, and in 3 others collections of metaplastic pyloric glands, some connected to the epithelium of the sinuses, were recognized. There was focal reactive atypia in both the epithelium of the surface and that of the sinuses. The R-A sinuses resembling gland-like structures had a laminar distribution rather than a disorderly haphazard distribution seen in well-differentiated adenocarcinoma. The remaining 3 cases misinterpreted as adenocarcinomas consisted of numerous deeply penetrating long and short R-A sinuses that branched in different directions and which reach the subserosal or perimuscular connective tissue mimicking invasion. The sinuses were surrounded by hyperplastic smooth muscle bundles and lined by pseudostratified columnar cells mixed with a few goblet cells showing reactive atypia and no mitotic figures. There was focal reactive atypia in both the epithelium of the surface and that of the sinuses. The 2 types of R-A sinuses did not label with carcinoembryonic antigen or p53 and had very low proliferative activity as measured by the MIB1-labeling index. All patients are alive and disease free from 8 months to 17 years (mean follow-up 7 y). In contrast, the foci of invasive adenocarcinoma that arose in R-A sinuses consisted of glands lined by atypical cuboidal or columnar cells with loss of polarity, large hyperchromatic or vesicular nuclei, prominent nucleoli, and mitotic figures, quite different from the cells lining the R-A sinuses. Because of increasing number of laparoscopic cholecystectomies performed annually in the United States, pathologists should become familiar with these gallbladder lesions that are usually incidental findings but can simulate malignant epithelial neoplasms.