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Background and Purpose: Prior studies regarding acute toxic leukoencephalopathy (ATL) are either small, or preliminary. Our aim was to evaluate etiologies of and differences in imaging severity and outcomes among various etiologies of ATL., Materials and Methods: MRIs of patients with suspected ATL over 15 years were retrospectively reviewed; inclusion criteria were: MRI <3 weeks of presentation with both DWI and FLAIR. These were jointly graded by two neuroradiologists via a previously described score of severity. Clinical outcome was evaluated via both modified Rankin (mRS) and ATL outcome (ATLOS) scores, each being correlated with the DWI and FLAIR scores. Etiologic subgroups of n > 6 patients were statistically compared., Results: Of 101 included patients, the 4 subgroups of n > 6 were the following: chemotherapy ( n = 35), opiates ( n = 19), acute hepatic encephalopathy ( n = 14), and immunosuppressants ( n = 11). Other causes ( n = 22 total) notably included carbon monoxide ( n = 3) metronidazole ( n = 2), and uremia ( n = 1). The mean DWI/FLAIR severity scores were 2.6/2.3, 3.3/3.3, 2.1/2.1 and 2.0/2.5 for chemotherapeutics, opiates, AHE and immunosuppressants, respectively, with significant differences in both imaging severity and outcome ( P = .003-.032) among subgroups, particularly immunosuppressant versus chemotherapy-related ATL and immunosuppressants versus opiates ( P = .004-.032) related ATL. DWI and FLAIR severity weakly correlated with outcome (ρ = 0.289-.349, P < .005) but correlated stronger in the chemotherapy (ρ = 0.460-.586, P < .010) and opiate (ρ =.472-.608, P < .05) subgroups, which had the worst outcomes. ATL clinically resolved in 36%, with severe outcomes in 23% (coma or death, 9/16 deaths from fludarabine). Notable laboratory results were elevated CSF myelin basic protein levels in 8/9 patients and serum blood urea nitrogen levels in 24/91., Conclusions: Clinical outcomes of ATL vary on the basis of etiology, being worse in chemotherapeutic- and opiate-related ATL. Uremia may be a predisposing or exacerbating factor., (© 2019 by American Journal of Neuroradiology.)