We sought to reduce tumor hypoxia by topical application of a vasodilator, benzyl nicotinate (BN), and investigated its effect on the growth of tumors irradiated at times when tumor pO₂ increased. EPR oximetry was used to follow the changes in the tissue pO₂ of subcutaneous radiation-induced fibrosarcoma (RIF-1) tumors during topical applications of 1.25–8% BN formulations for 5 consecutive days. The RIF-1 tumors were hypoxic with a tissue pO₂ of 4.6–7.0 mmHg. A significant increase in tumor pO₂ occurred 10–30 min after BN application. The formulation with the minimal BN concentration that produced a significant increase in tumor pO₂ was used for the radiation study. The tumors were irradiated (4 Gy × 5) at the time of the maximum increase in pO₂ observed with the 2.5% BN formulation. The tumors with an increase in pO₂ of greater than 2 mmHg from the baseline after application of BN on day 1 had a significant growth inhibition compared to the tumors with an increase in pO₂ of less than 2 mmHg. The results indicate that the irradiation of tumors at the time of an increase in pO₂ after the topical application of the 2.5% BN formulation led to a significant growth inhibition. EPR oximetry provided dynamic information on the changes in tumor pO₂, which could be used to identify responders and non-responders and schedule therapy during the experiments.