The most recent clinical practice guidelines released by Cancer Australia draw attention to unanswered questions concerning the health economic considerations associated with hypofractionated radiotherapy. This study aimed to quantify and compare the healthcare costs at a regional Australian radiotherapy institute with respect to conventionally fractionated post-mastectomy radiotherapy (Cf-PMRT) versus hypofractionated post-mastectomy radiotherapy (Hf-PMRT) administration.Medical records of 196 patients treated with post-mastectomy radiotherapy at the NSW North Coast Cancer Institute from February 2008 to June 2014 were retrospectively reviewed. Australian Medicare item numbers billed for patients receiving either Cf-PMRT of 50 Gy in 25 daily fractions or Hf-PMRT of 40.05 Gy in 15 daily fractions were calculated. Decision tree analysis was used to model costs. Independent-samples t-tests and Mann-Whitney U-tests were used to compare crude average costs for Cf-PMRT and Hf-PMRT and determine which treatment components accounted for any differences.Hf-PMRT, with or without irradiation to the regional lymph nodes, was associated with significantly reduced Medicare costs ($5613 AUD per patient for Hf-PMRT vs $8272 AUD per patient for Cf-PMRT; P < 0.001). Savings associated with Hf-PMRT ranged from $1353 (22.1%) for patients receiving no regional irradiation to $2898 (32.0%) for patients receiving both axillary and supraclavicular therapy.Hf-PMRT results in a significant reduction in the financial costs associated with treating breast cancer patients in a regional Australian setting when compared with Cf-PMRT.