Oxaliplatin immune-induced syndrome (OIIS) is an uncommon, potentially life-threatening, side effect associated with oxaliplatin-based chemotherapy. The present study reports 5 original cases of OIIS and systematically reviewed the available published cases. We retrospectively analyzed the clinical archives of the Niguarda Cancer Center from 2009 to 2015 and conducted a search for OIIS using the PubMed database, followed by deeper investigation of the references of the recorded studies. We pooled our series with other reported cases for systematic review in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement using only English language as the selection criterion. A total of 61 OIIS cases were analyzed, the largest series reported to date. Of the 61 patients, 56 (91.8%) had received oxaliplatin for metastatic colorectal cancer. In 32 of the 61 patients (52.5%), OIIS was associated with grade 4 thrombocytopenia and in 4 (6.6%) with grade 4 anemia. OIIS was fatal in 4 patients. In 49 patients, oxaliplatin-induced immune system activation was tested using the Coombs test or by detection of antiplatelet antibodies and was positive in 87.7% of the patients. The average number of oxaliplatin cycles until the onset of OIIS was 16.7, and the number was significantly lower when oxaliplatin was administered as a rechallenge after a period of vacancy of treatment with this agent (4.6 cycles as rechallenge vs. 13.6 as first-time exposure; P < .00001). OIIS is triggered by cumulative administration of oxaliplatin, characteristically with a threefold earlier onset when the drug is administered as a rechallenge. Prompt identification of OIIS can be expected to reduce the risk of iatrogenic morbidity and mortality.