Interactions between host and malignant tumor is currently under intensive investigation. The immune system seems to have a key role in cancer development and spread. Novel strategies to actively modulate the immune system have been proposed to improve the outcome of disease in patients with neoplasms. Our experience with systemic immunomodulation by interleukin-2 (IL-2) focused on both systemic and local immunity in surgical gastrointestinal cancer. Preoperative IL-2 subcutaneous injection was effective in counteracting postoperative immunosuppression, with a reduction of serum levels of IL-6 and the maintenance of preoperative levels of IL-12, a higher number of circulating total lymphocytes, and CD3(+) and CD4(+) T-cells, and a smaller decrease in circulating mature and immature dendritic cells (DCs), as well as a reduction in postoperative serum levels of vascular endothelial growth factor. At the intestinal level, in patients with colorectal cancer, preoperative administration of IL-2 affected both phenotype and function of resident dendritic cells and T-cells, skewing local immunity toward a more immunogenic one. Our data showed that immunomodulation by IL-2 was effective in counteracting the systemic postoperative immune suppression related to surgical stress. IL-2 was also active at a local level on intestinal immunity, affecting both phenotype and function of resident T-cells and DCs. Future studies will encompass the possibility of reaching more adequate intratumoral IL-2 concentrations by direct intralesional injection to maximize immunostimulatory effects and minimize adverse effects.