Exposure to ionizing radiation emitted from natural sources induces many health hazards. The response to ionizing radiation involves a number of mediators including inflammatory cytokines and free radicals which mediate immunosuppression. The present study aimed to monitor the impact of exposure to natural radioactive rocks from the Egyptian eastern desert on the primary immune organs. Therefore, three experimental groups (15 rats per group) were used: group I included the control non-irradiated rats; group II included rats that were exposed for 28 consecutive days to natural radioactive rocks from the Egyptian eastern desert (IR/R group); and group III (positive control group) included rats that were exposed to high dose of γ-rays (4 Gy/14 days for 28 days) (IR/γR group). We found that rats of both the IR/R and IR/γR groups exhibited pathological alterations in the architecture of the primary immune organs (bone marrow and thymus). Additionally, the levels of C-reactive protein (CRP), proinflammatory cytokines (IL-1β, IL-6 and TNF-α), and reactive oxygen species (ROS) were significantly increased in the IR/R and IR/γR groups compared to the control group. Furthermore, rats from the IR/R and IR/γR groups exhibited significant increase in the activity of caspase-3 and caspase-9 and subsequently exhibited a significant increase in the apoptosis of PBMCs compared with the control group. Most importantly, apoptosis induction in the PBMCs was associated with increased expression of cyclin B1 and decreased expression of cyclin D1 and survivin compared with the control non-irradiated group. Taken together, our data demonstrated that consecutive exposure to natural radioactive rocks from the Egyptian eastern desert could dampen the immune response through damaging the architectures of the immune system and mediating serious health problems to the population inhabiting this region.