Several hazardous substances, can damage our DNA in various ways. Defining these substances and the protective ones is very important. Therefore, researches have increased on various compounds based on natural sources which keep the harmful effects of these various agents at the minimum level. In the present study, we evaluated the potential genotoxic/ antigenotoxic/ antimutagenic activity of the crude chloroform: methanol (2:1) extracts of Hypnea musciformis (Wulfen) Lamouroux (HME), in human lymphocytes culture in vitro against genotoxic/ mutagenic agents mitomycin C (MMC) and ethyl methanesulfonate (EMS) by using chromosome aberration (CA), sister chromatid exchange (SCE) and micronuclei (MN) assays, and also determined total antioxidant capacity (in soluble lipid and water), phenolic compound, protein, carbohydrate, vitamins (A, C and E) contents. The frequency of chromosome aberrations and SCE increased by MMC, were significantly decreased by HME (p < 0.05 for CA, p < 0.001 for SCE). The MN frequencies of the cells were significantly decreased by the treatment with HME plus MMC or EMS when compared with the positive controls (MMC or EMS) (p < 0.05). In conclusion, HME itself is not a clastogenic or cytotoxic substance. On the other hand, HME possesses a strong antigenotoxic, anti-clastogenic and protective effects against MMC in vitro.