While targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, patient bene t with OXPHOS inhibitors in the clinic has yet to be achieved. Based on promising preclinical data, we advanced IACS-010759, a highly potent and selective small-molecule inhibitor of mitochondrial complex I, into two phase I trials in patients with acute myeloid leukemia (NCT02882321) or advanced solid tumors (NCT03291938). Clinical ndings revealed that IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities that included elevated blood lactate and neurotoxicity, obstructing efforts to maintain target plasma exposure. Consequently, only modest on-target inhibition and limited antitumor activity were observed. Follow-up reverse translational studies uncovered that IACS-010759 reduced oxygen consumption rates in neurons and damaged myelin. Further, IACS-010759-treated mice displayed behaviors indictive of neuropathy, which were minimized with the co-administration of a histone deacetylase 6 inhibitor. Our ndings urge caution in the continued development of complex I inhibitors as antitumor agents.