The in vitro effect of small peptides on the nonspecific immune response of sea cucumber, Apostichopus japonicus, coelomocytes was studied. Coelomocytes were cultured in L-15 medium containing different concentrations of small peptide (0, 5, 25, and 100 g/mL). Coelomocytes were incubated with the above immunostimulant for 1, 3, 6, 12, and 24 h. Coelomocytes incubated in the medium without immunostimulants were taken as controls at each incubation time. After exposure to small peptides, the coelomocytes were sampled and immune parameters namely, phagocytosis activity, respiratory burst activity, as well as activities of acid phosphatase (ACP), alkaline phosphatase (AKP), and superoxide dismutase (SOD) were determined. All immune parameters were significantly (P < 0.05) enhanced by small peptides. Both phagocytic capacity and respiratory burst activity were up to maximum values at 6 h, and these values were 1.6 and 1.1 times as high as the control group, respectively. Among the humoral responses, the activities of ACP, AKP, and SOD were also up to maximum values at 6 h. The values were 1.4, 1.3, and 1.4 times as high as the control group, respectively. These results suggest that small peptides can enhance the nonspecific immune response of sea cucumber in vitro.