The purpose of this study was to analyze the combined effects of regular exercise and ginseng supplementation on peritoneal exudate ROS (reactive oxygen species), lymphocyte proliferation by splenocytes, and DNA damage following exhaustive exercise stress. Thirty-six female BALB/c mice were randomly divided into control (UT, n = 12), trained (TR, n = 12), and ginseng supplemented and trained (GT, n = 12) groups. Each group was divided into two equal subgroups where mice were studied at rest (UTre, TRre, and GTre) or immediately after exhaustive exercise stress (UTex, TRex, and GTex). Animals were bred in the animal facility, where they were housed at 22-24 degrees C and relative humidity (RH) 50-60% in a controlled environment with a 12-hour photoperiod, and provided food and water ad libitum. The trained mice underwent 10 weeks of endurance swim training (5 times/week) in water at 27-30 degrees C for 60 minutes. The analytical items examined were weight, proliferative activity, the production of ROS from peritoneal exudate cells, and DNA damage following exhaustive exercise stress (2 h exercise stress). Significant level was set at p < 0.05. The results obtained showed that the trained group had a significantly lower mean body weight than the untrained group (p < 0.05). However, there was no significant difference between UT and GT. Swim training increased swim survival time in TRex and GTex, and TRex showed the highest swim survival time. With regard to mitogenic activities of splenocytes in response to exhaustive exercise stress, all groups showed much lower lymphocyte proliferative activity when stimulated with media (Med), concanavalin A (ConA), or lipopolysaccharide (LPS) after exhaustive exercise stress. However, GTex had a higher proliferative activity than the other groups. Trained and ginseng-supplemented groups showed lower peritoneal ROS responses and lymphocyte DNA damage levels after exhaustive exercise. These findings suggest that the combined effect of swim training and ginseng supplementation sustain lymphocyte function in the presence of reduced ROS production and DNA damage following acute exercise stress.