Introduction: The use of programmed death-ligand 1 (PD-L1) checkpoint inhibitor therapy is expanding, although its adverse effects are not completely known. We report on a rare case of acute cytokine release syndrome related to pembrolizumab use in a patient with lung cancer. Case report: A 79-year-old man with metastatic, PD-L1-positive, non-small-cell lung cancer developed a febrile condition associated with a systemic inflammatory response syndrome and suffered haemodynamic compromise four hours after the first intravenous administration of pembrolizumab. A thorough medical workup found no alternative cause and a grade 2 cytokine release syndrome (CRS) was diagnosed. Management and outcome: Aggressive fluid resuscitation and supportive therapy led to restitutio ad integrum. Discussion: Acute CRS after the administration of a PD-L1 inhibitor is infrequent but could be a fatal condition. Supportive treatment and, if necessary, corticosteroids should be considered.