In cancer therapy, Mitomycin C (MMC) is a commonly used drug to fight several human malignancies; it is a powerful anti-bacterial and anti-tumor fungal antibiotic. However, during clinical use several side effects may occur. The current study was designed to investigate the potential effect of pre- and post- addition of Spirulina platensis (Sp) to the diet on mitomycin C (MMC) induced genotoxic and molecular alterations. Sixty Ehrlich Ascites Carcinoma Cell (EAC) bearing female albino mice (i.p injection of 2.5x106 EAC cell/ mouse) were classified into six groups which received different treatment of SP powder 1% in diet and MMC (i.p. 1mg/kg BW). After 7 days from MMC injection, specimens were collected for evaluation of DNA damage using comet assay and transcriptional estimation of mutant apoptotic P53 and glutathione peroxidase mRNA expression level by semiquantitative (RT-PCR). Results showed that MMC induced a genotoxic effect in mice bone-marrow and liver cells, SP significantly reduced the level of DNA damage and augmentation of expression levels of studied genes mRNA. In conclusion, our results confirm the antigenotoxic potential of SP and provide strong evidence to support administration of SP during MMC-therapy.