Background: Antioxidants have the potential to protect normal tissues against radiation-induced damage, but must not protect tumor cells during radiotherapy. The major objectives were to determine whether a metalloporphyrin antioxidant affects prostate tumor response to radiation and identify possible mechanisms of interaction. Materials and Methods: C57BL/6 mice with RM-9 tumor were treated with manganese (III) meso-tetrakis(1,3-diethylimidazolium-2-yl) porphyrin (MnTDE-2-ImP) and 10 gray (Gy) radiation. Tumor volume was quantified and a subset/group was evaluated for hypoxia-inducible factor-1α (HIF-1α), bone marrow-derived cell populations and cytokines. Results: The addition of MnTDE-2-ImP transiently increased tumor response compared to radiation alone. The group receiving drug plus radiation had reduced intratumoral HIF-1α and decreased capacity to secrete TNF-α, whereas production of IL-4 was increased. There were no toxicities associated with combination treatment. Conclusion: The results demonstrate that MnTDE-2-ImP did not protect the RM-9 prostate tumor against radiation; instead, radiation effectiveness was modestly increased. Possible mechanisms include reduction of radiation-induced HIF-1α and an altered cytokine profile.