Colorectal cancer (CRC) is associated with chronic inflammation and immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Although chemotherapy reduces tumor burden at early stages, it tends to have limited effect on a progressive disease, possibly due to adverse effects on the immune system in dictating disease outcome. Here we show that advanced CRC patients display enhanced MDSC levels, reduced CD247 expression and that some conventional CRC chemotherapy supports the immunosuppressive tumor microenvironment. A FOLFOX combined therapy reduced immunosuppression whereas a FOLFIRI combined therapy enhanced immunosuppression. Mechanistic studies in a CRC mouse model revealed that FOLFIRI-like therapy including the drugs CPT11 and 5FU damaged host immune competence in a manner that limits treatment outcomes. CPT11 blocked MDSC apoptosis and myeloid cell differentiation, increasing MDSC immunosuppressive features and mouse mortality. In contrast, 5FU promoted immune recovery and tumor regression. Thus, CPT11 exhibited detrimental immunoregulatory effects that offset 5FU benefits when administered in combination. Our results highlight the importance of developing therapeutic regimens that can target both the immune system and tumor in developing improved personalized treatments for CRC.