Total laparoscopic hysterectomy (LH) is a minimally invasive technique, which results in comparable morbidity and better cosmesis compared with total abdominal hysterectomy. The literature is discrepant as to whether it is associated with a higher incidence of positive peritoneal cytology compared with total abdominal hysterectomy and recently, associated artifacts, including vascular pseudoinvasion (VPI), have been described. A retrospective histopathologic review of 266 hysterectomy specimens from 2 centers was performed. The observers, blinded to the surgical technique, assessed for the presence of artifactual changes including disruption of the endometrial lining, nuclear crush artifact, VPI, endomyometrial cleft artifact with or without epithelial displacement, inflammatory debris within vessels, serosal carryover, and intratubal contaminants. In addition, the rates of positive peritoneal washings over a 5-year period, and the use of immunohistochemistry (IHC) to aid in cell typing over a 3-year period, were compared between hysterectomies in which a uterine manipulator (UM) device had and had not (nonmanipulated hysterectomies) been used. The hysterectomies were performed for malignant (n=160) and benign (n=102) uterine disease or for ovarian or cervical disease (n=4), and included total abdominal (n=108), vaginal (n=17), laparoscopy-assisted vaginal (n=24), laparoscopy converted to laparotomy (n=10), nonrobotic laparoscopic (n=51), and robot-assisted laparoscopic (n=56) hysterectomies. One hundred and two (38%) of these hysterectomies involved the use of a UM. Artifactual changes of disruption of the endometrial lining, endomyometrial clefts, intratubal contaminants, nuclear crush artifact, intravascular inflammatory debris, and VPI were significantly more common with LH and with the use of a UM, independent of whether the endometrial pathology was benign or malignant. IHC to aid in endometrial cancer subtyping was more likely to be used in manipulated hysterectomies (P=0.0166). Furthermore, peritoneal washings were significantly more likely to be positive in hysterectomies in which a UM had been used (P=0.0061). Histologic artifacts are significantly more common in LH and specifically in hysterectomies in which a UM is used. Such artifacts impair the pathologists' interpretation of cell type requiring an increased use of IHC, and displaced epithelial fragments present within vessels or artifactual clefts may result in the misinterpretation of prognostic and staging parameters. Furthermore, there is a significantly higher rate of positive peritoneal cytology in cases that are subjected to uterine manipulation, suggesting dissemination of malignant cells into the abdominal cavity. The clinical significance of this finding needs to be determined.