Abstract Background: Exercise could change the immune system. It is illustrated that abnormal environments are the primary source of physiological stresses which can disarrange the function of immune system. The purpose of this study was to investigate the effects of high volume exercise (HVE) in hypoxia and normoxia conduction on the immune system response in selected inactive men. Materials and methods: In this study, eighth inactive young men (age 25.50±5 years, height 174±5.4 cm, weight 62 ±4.5 kg, and maximum work output in hypoxia conduction 159±13.41 and in normoxia conduction 171±8.21) were selected as subjects. Subjects performed protocol of high-endurance exercise in normobaric hypoxia conduction (15.3%-15.5% O2, an altitude of approximately 2500 m) and normoxia in two separate weeks. Blood samples was taken immediately before and two hours after exercise. Results: The results of ANOVA method (repeated measures) was explained that environmental conditions can’t cause significant differences in the number of white blood cells. But other hematology variables have been significantly changed, in neutrophil levels (P=0.013), lymphocytes (P=0.001), platelets (P=0.012), and hematocrit (P=0.037). When variations between groups was evaluated, it was shown that only white blood cells had a significant change in both conditions, but the other variables have significant changes only in hypoxic condition. Conclusion: Our results showed that endurance exercise in 2500 m height has drastic effect on immune system factors and this situation was obviously dominant in hypoxia versus normoxia conduction.