Background: Management of head and neck cancer includes surgical resection, chemotherapy and radiotherapy (RT). We hypothesized that pre-radiation treatment with a mineralocorticoid receptor (MR) antagonist, spironolactone (S), may have radioprotective effect on salivary glands. Materials and Methods: Study included 30 adult female Wistar albino rats. Rats were divided into four groups (G); G1, control group; G2, RT-only group, G3, S-only group; G4, RT plus S group. Rats were sacrificed at 6th hour; 21st and 100th days after RT. Salivary gland samples were taken for microscopical examination. Results: Periductal-perivascular inflammation scores in 21st and 100th days tended to be higher in G2 than in G4, but the difference was not statistically significant. Periductal-perivascular fibrosis score was significantly different between the groups in 100th day (P: 0.010). Pairwise comparisons revealed that periductal-perivascular fibrosis scores were different between G1 and G2 (P: 0.014), G2 and G3 (P: 0.014), G2 and G4 (P: 0.034). Conclusions: MR blockade with S, when initiated before RT, ameliorates late radiation-induced fibrosis in the submandibular glands.