There is considerable epidemiological evidence indicating an association between diets rich in fresh fruit and vegetables and a decreased incidence of cancers. Methyl methanesulfonate (MMS) and cyclophosphamide (CP) are alkylating agents that differ in their mode of action. MMS is a directly-acting, monofunctional agent, while CP is a bifunctional agent that requires metabolic activation to a reactive metabolite. To evaluate if orange juice could reduce DNA damage induced by these alkylating agents, mice were treated orally (by gavage) with MMS and CP, prior to and after treatment with orange juice. DNA damage was evaluated by the comet assay in peripheral white blood cells. Under these experimental conditions, orange juice reduced the extent of DNA damage caused by both mutagens. For MMS, the antigenotoxic effect of the orange juice was both protective (orange juice pre-treatment) and reparative (orange juice post-treatment); for CP, the effect was reparative only. The components of orange juice can have several biological effects, including acting as targets of toxicants and modulating metabolization/detoxification routes. Considering the different mechanisms of the action of the two drugs, different protective effects are suggested. These results demonstated the ability of the in vivo comet assay to detect in vivo modulation of MMS and CP mutagenicity by orange juice.