A glycoprotein prepared from Chlorella vulgaris culture supernatant (CVS) is a biological response modifier (BRM) which exhibits protective activities against tumor metastasis and 5-fluorouracil-induced immunosuppression. We here show that oral administration of CVS prevented significantly the apoptosis of thymocytes in mice undergoing psychological stress in a communication box. Mice were exposed to the emotional stress for 14 days by witnessing other mice being exposed to foot-shock. The numbers in thymocytes, especially CD4(+)CD8(+) population, were decreased significantly and apoptotic cells, as assessed by Annexin V expression, were reciprocally increased after the exposure to the psychological stress. C. vulgaris culture supernatant (CVS) administration significantly suppressed the increase in serum corticosterone level in the psychologically stressed mice. These results suggest that CVS prevents psychological stress and maintain homeostasis in the face of external environmental changes.