This investigation compared how various exercise regimens with/without hypoxia influence the phenotypic characteristics of blood natural killer cells (NKs) subsets and the cytotoxicity of NKs to nasopharyngeal carcinoma cells (NPCs). Sixty sedentary males were randomly divided into five groups. Each group (n=12) underwent one of five interventions - normoxic (21%O2) resting, hypoxic (15%O2) resting, normoxic exercise (50%Wmax under 21%O2, N-E), hypoxic-relative exercise (50% maximal heart rate reserve under 15%O2, H-RE), or hypoxic-absolute exercise (50%Wmax under 15%O2, H-AE) for 30 minutes/day, five days/week for four weeks. Our results showed that both H-AE and H-RE for four weeks up-regulated the expressions of co-stimulatory (CD28)/memory (CD45RO)/activating (NKG2D) molecules on NKs, which effect was accompanied by depressed the levels of NKs-expressing CD57/KLRG1 in blood. The two regimens increased NK perforin/granzyme B contents and the NK-induced apoptosis (phosphotidylserine exposure) of NPCs at rest and following the exercise. However, no significant change in the phenotypic characteristics of blood NK subsets or NK-induced NPC apoptosis was observed following the N-C, H-C, and N-E interventions. Therefore, we conclude that both H-AE and H-RE regimens increase the levels of the NKs-expressing co-stimulatory/memory/activating molecules and cytotoxic granule proteins in blood, increasing the anti-NPC cytotoxicity capacity of NKs.