Due to the cytotoxic effect of antimicrobial peptides (AMP) against several microorganism and tumor cells has been proposed their association with the immune system. However, just a few reports have shown this relationship. In this study, mice were treated with gomesin, a β-hairpin AMP that exhibit high cytotoxicity against bacterial and tumor cells. Different effects in the immune system were observed, such as, decrease of CD3+ in T lymphocytes (Control: 17.7 ± 1.4%; Gomesin: 7.67 ± 1.2%) and in hematopoietic progenitors and increase of hematopoietic stem cell (Control: 0.046 ± 0.004%; Gomesin: 0.067 ± 0.003%), B220+ B lymphocytes (Control: 38.63 ± 1.5%; Gomesin: 47.83 ± 0.48%), and Mac-1+F4/80+ macrophages (Control: 11.76 ± 3.4%; Gomesin: 27.13 ± 4.0%). Additionally, macrophage increase was accompanied by an increase of macrophage phagocytosis (Control 20.85 ± 1.53; Gomesin 31.32 ± 1 Geometric mean), interleukin 6 (Control: 47.24 ± 1.9 ng/mL; Gomesin: 138.68 ± 33.68 ng/mL) and monocyte chemoattractant protein-1 (Control: 0.872 ± 0.093 ng/mL; Gomesin: 1.83 ± 0.067 ng/mL). Thus, this report showed immunomodulatory activity of gomesin in the immune system of mice.