Cadmium being a potent immunotoxicant, affects both humoral and cell mediated immunity. In rodents, it is primarily characterized by marked thymic atrophy and splenomegaly. Cadmium induces apoptosis in mice and suppresses the immune functions. Piperine, major alkaloid of Piper longum Linn. and Piper nigrum Linn. with a long history of medicinal value, has shown anti-apoptotic activity in vitro. Thus, to delineate its role in vivo, piperine (2.5mg/kg/day, oral, 7 days) treated Balb/C mice were administered Cd as CdCl(2) (1.8mg/kg, i.p., once, 4th day). The various biochemical indexes of cell damage such as cytotoxicity (MTT assay), oxidative stress (glutathione, reactive oxygen species), apoptosis (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) along with lymphocyte phenotyping, cell proliferative response and cytokine secretion (IL-2 and IFNγ) were assessed in thymic and splenic single cell suspensions. Lowering of body weight gain and cellularity and a loss in cell viability seen in Cd group, were abrogated by piperine treatment. Similarly, oxidative stress and apoptotic markers altered by Cd were also modulated by this alkaloid. In addition, a pronounced inhibition of cell proliferative response, alterations in T- and B-cell phenotypes, cytokine release and morphological changes were restored to normalcy. The present in vivo data corroborating with our previous in vitro findings, provide confirmatory evidence of the immuno-protective efficacy of piperine.