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Background: Radioprotective effects of melatonin and famotidine were reported in previous studies. In this study, modulating effects of these agents alone or in combination were tested on high dose radiation induced cell lethality in MRC5 and Hela cells. Materials and Methods: DPPH (2,2-Diphenyl-1-picrylhydrazyl) was used to measure antioxidant property of famotidine and melatonin at different concentrations. Famotidine at a concentration of 80 µg/ml and melatonin at a concentration of 80 µg/ml was added to culture flasks containing MRC5 and Hela cells two hr prior to gamma-irradiation. Treated and untreated cells were irradiated with doses of 4 and 8 Gy gamma-rays. MTT assay was used to measure cell viability 48 and 72 hours after irradiation. Data were analyzed using nonparametric one way analysis of variance (ANOVA). Results: DPPH assay showed high antioxidant potential for melatonin. Presence of melatonin led to significant elevation of cell viability of both MRC5 and Hela cell lines after 4 and 8 Gy gamma-irradiation at both sampling times (p<0.01). However, for Hela cells exposed to 4 Gy, melatonin led to reduced cell viability (p<0.05). Famotidine, did not improve radiation induced cell lethality for both MRC5 and Hela cells exposed to 4 and 8 Gy. Conclusion: Except for 4 Gy irradiated Hela cells, presence of melatonin led to a significant radioprotection against radiation induced cell lethality of cells, Famotidine failed to improve cell viability in both cell lines. The mechanism of radioprotection of melatonin might be attributed to its radical scavenging potential.