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Purpose Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with its possible neuroprotective and anti-inflammatory effects reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo controlled trial in mCRC patients receiving first line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI).Methods We randomly assigned 70 mCRC patients to FOLFOXIRI plus δ-tocotrienol or FOLFOXIRI plus placebo. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo x 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy.Results Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio (HR) of 0.70 (95% CI 0.36-1.36, p=0.29)). In the placebo group 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p=0.047).Conclusion The addition of δ-tocotrienol to FOLFOXIRI did not significantly prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different between the two groups. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.Clinicaltrials.gov identifier NCT02705300. Date of registration March 10, 2016.