PURPOSE: To compare clinical outcomes of image-based versus non-image-based interstitial brachytherapy (IBBT) for vaginal cancer. METHODS AND MATERIALS: Of 72 patients with vaginal cancer treated with brachytherapy (BT), 47 had image guidance (CT=31, MRI=16) and 25 did not. Kaplan-Meier (KM) estimates were generated for any recurrence, local control (LC), disease-free interval (DFI), and overall survival (OS) and Cox models were used to assess prognostic factors. RESULTS: Median age was 66 and median follow-up time was 24months. Median cumulative EQD2 dose was 80.8Gy in the non-IBBT group and 77Gy in the IBBT group. For non-IBBT versus IBBT, the 2-year KM LC was 71% vs. 93% (p=0.03); DFI was 54% vs. 86% (p=0.04); and OS 52% vs. 82% (p=0.35). On multivariate analysis, IBBT was associated with better DFI (HR 0.24, 95% CI 0.07-0.73). Having any 2 or more of chemotherapy, high-dose-rate (HDR) BT or IBBT (temporally correlated variables) significantly reduced risk of relapse (HR=0.33, 95% CI=0.13-0.83), compared to having none of these factors. CONCLUSION: Over time, the use of chemotherapy, HDR, and IBBT has increased in vaginal cancer. The combination of these factors resulted in the highest rates of disease control. Image-guided brachytherapy for vaginal cancer patients maximizes disease control.