OBJECTIVE: To identify preoperative risk factors associated with vaginal cuff dehiscence after total hysterectomy. The secondary objective was to identify intraoperative and postoperative risk factors for vaginal cuff dehiscence. METHODS: A multicenter retrospective case-control study, matched 1:3, of women who underwent total hysterectomy was performed on charts from July 2000 through July 2012. The following variables were collected: preoperative characteristics, surgical information, and up to 6 weeks of postoperative data. RESULTS: Five sites collected 35 cases of vaginal cuff dehiscence after hysterectomy and 105 controls. The following preoperative characteristics were not associated with vaginal cuff dehiscence (not listed in Table 1 for brevity): parity, COPD, asthma, oral steroid use, diabetes mellitus, autoimmune disease, connective tissue disorder, current chemotherapy/radiation, leukocytosis menorrhagia, fibroids, endometriosis, and chronic pelvic pain . Multivariate logistic regression analysis showed the following variables to be risk factors for dehiscence: anemia (AOR 1.53, CI 1.09, 2.34), laparoscopic assisted vaginal hysterectomy (LAVH) route (AOR 14.68, CI 5.67, 38.01), total laparoscopic hysterectomy (TLH) route (AOR 73.00, CI 16.71, 318.96), postoperative pelvic hematoma (AOR 8.00, CI 2.73, 23.45), and postoperative pelvic abscess (AOR 11.95, CI 4.301, 33.13). The following variables were protective against vaginal cuff dehiscence: pelvic organ prolapse as an indication for hysterectomy (AOR .16, CI .068, .38), obesity (AOR .31, CI .21, .46), bipolar colpotomy (AOR .18, CI .040, .84), and laparoscopic cuff closure route (AOR .29, CI .089, .92). CONCLUSIONS: Our findings suggest that preoperative anemia, LAVH and TLH routes, postoperative pelvic hematoma and abscess increase the risk of cuff dehiscence after hysterectomy. Obesity, use of bipolar cautery for colpotomy, and laparoscopic route of cuff closure are protective against dehiscence. The mixed biologic plausibility of these findings suggests the need for greater numbers in future research to better understand these associations.