The monoterpene D-limonene and its metabolites have been shown to exert chemopreventive and chemotherapeutic activities against different tumors in animal models and clinical trials. However, it is unknown whether these compounds modulate the immune response in tumor-bearing mice. We evaluated the survival of lymphoma-bearing mice fed with a diet with D-limonene. To assess the cell immune response, we sensitized and challenged BALB/c mice with 2,4-dinitrofluorobenzene (DNFB) and evaluated the T-cell subpopulations by flow cytometry. We also examined phagocytosis, microbicidal activity and chemotactic function in peritoneal macrophages. In order to know the role of D-limonene and its metabolites, macrophage NO production and lymphocyte proliferation studies were performed in vitro with D-limonene, perillic acid and perillyl alcohol. The results showed that D-limonene increased the survival of lymphoma-bearing mice, delayed hypersensitivity reaction to DNFB, phagocytosis and microbicidal activity. In vitro studies indicate that D-limonene increased NO production in peritoneal macrophages obtained from tumor-bearing mice. Our data suggest that in addition to reported properties, D-limonene modulates the immune response with significant potential for clinical application.