The heavy metal lead is an environmental toxic material that can induce pathophysiological changes in many organ systems. Previous studies have shown the effects of lead exposure on immune cells in different experimental animals, however, the mechanism of their influence on the immune system is unclear. We reported that in vivo lead exposure inhibits phagocytosis, nitric oxide release, induces DNA fragmentation suggesting the apoptotic death of the target cell. We have also presented evidence that inhibition of macrophage functional responses implicated alteration of humoral and cell mediated immunity. In vivo exposure to lead acetate alters the phagocytic capacity of splenic macrophages as evident from the reduction of phagocytic index of control from 19,792 ± 1385.69 to 8893 ± 893 in the treated group. The amount of nitric oxide released by the control cell 2.25 ± 0.125 μM is also reduced to 1.9375 ± 0.0625 μM upon in vivo lead treatment. Functional integrity of the target cell is also decreased after lead exposure as obtained from the percentage of DNA fragmentation. Control group shows 33.29 ± 0.11% of fragmented DNA, which is enhanced to 42.43 ± 0.725% following the lead treatment. A greater percentage of DNA fragmentation upon lead treatment probably indicating that the heavy metal induces apoptosis. The humoral immune response is also altered after lead exposure as indicated by the decrease of the antibody titre in control group from 1:2048 to 1:128 in the treated group. From the DTH reaction, it was observed that the mean diameter of swollen foot pad of control mice is 0.329 ± 0.15 cm and that of lead treated mice is 0.274 ± 0.056 cm. It can, therefore, be suggested that lead inhibits normal functional activities of splenic leukocytes, particularly phagocytosis and also affects the functional integrity of cells by inducing DNA fragmentation. The study may demonstrate the usefulness of investigation of humoral immune system and leukocyte functions as sensitive parameters in detecting the effects of lead toxicity.