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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 24 months. Median cumulative EQD2 dose was 80.8 Gy in the non-IBBT group and 77 Gy 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.