A novel melanin with low molecular weight (LIM205, 522Da) was isolated from the fermentation broth of Lachnum sp. and its carboxymethyl derivative (CLIM205) was prepared. The immunoregulatory effects of LIM205 and CLIM205 in immuno-compromised mice induced by cyclophosphamide were investigated. The results demonstrated that both LIM205 and CLIM205 could significantly increase the thymus and spleen indices, specific and nonspecific (including carbon clearance ability) immunity, humoral and cellular immunity of mice. Treatment with LIM205 and CLIM205 could increase activities of SOD, GSH-PX, CAT and decrease content of MDA in the mice. Furthermore, for all animal tests, the immunoregulatory activities of CLIM205 were more prominent than that of LIM205. In conclusion, our findings suggested that the natural products LIM205, as well as its carboxymethyl derivative CLIM205, had significant immunoregulatory activities, which might be a promising source of immunoregulator in healthcare field.