Cytokine release syndrome (CRS) is an infrequently described immune-related adverse event of checkpoint inhibitors (CPI). CPI-induced CRS typically presents with fevers, hemodynamic instability and organ dysfunction within 2 weeks of the last treatment cycle. We report an unusual case of delayed and severe CRS occurring postoperatively in a patient with hepatic-limited metastatic colorectal cancer who received neoadjuvant immunotherapy. After a negative workup for alternative causes, he received prolonged corticosteroid treatment with symptom resolution. CPI-induced CRS can mimic sepsis and clinicians should maintain a high-index of suspicion to diagnose this immune-related adverse event early and initiate appropriate treatment. As use of perioperative immunotherapy increases, the potential role of surgery to trigger CRS in this case warrants further investigation.