The objective of this study was to investigate the effects of hot water extracts of Chlorella vulgaris (CVE) on a deteriorated immune function through utilization of a protein-energy malnutrition (PEM) diet. Unicellular algae, C. vulgaris, were used as biological response modifier. PEM is associated with decreased host immune defense. Male C57BL/6J mice, initially four weeks old, were fed for 8 days with standard diet or a PEM diet. Mice in the PEM diet group were orally administered 0.1 g/kg and 0.15 g/kg of CVE for the following week. Nutritional parameters such as the total protein, albumin, glucose, and interferon γ (IFN-γ) were increased in blood serum of the CVE-treated group compared with the non-treated group. The mononuclear cell numbers from spleen, superficial, and mesenteric lymph node were reduced in mice fed with PEM diet, but numbers from the spleen and superficial lymph node were increased by the CVE (0.1 and 0.15 g/kg) treatment. We also investigated the effect of CVE on the production of cytokines in human T-cell line, MOLT-4 cells, and primary cultured splenocytes. The CVE treatment significantly increased the production of both interleukin (IL)-2 and IL-4 compared with the media control, but did not affect the production of IFN-γ. These results suggest that CVE may be useful in improving the immune function.