This study compares the aetiology of pansteatitis in Lake Loskop, relative to two other impoundments along the Olifants River. Macroscopic and microscopic pathology, age determination and analysis of stomach content, fatty acids and stable isotopes explain the high prevalence of pansteatitis in Oreochromis mossambicus (Peters) and several other species in Lake Loskop. All the dietary indicator comparisons between pansteatitis-affected and healthy fish fail to support a systemic cause. Pansteatitis in Lake Loskop was linked to size and weight of O. mossambicus, but not to ontogenic age. Fish in Lake Loskop showed abnormally high omega-3 to omega-6 fatty acid ratios normally only found in marine fish with no significant difference in degree of assimilation of these fatty acids between pansteatitis-affected and healthy fish. This explains the vulnerability to, but not the occurrence of, pansteatitis. As a cause for the pansteatitis, these results point towards sporadic vitamin E-depleting trigger events, known sporadic fish die-off occurrences that provide surviving fish with a rich source of rancid fats on which to scavenge. The mechanism ties pansteatitis to eutrophication and trophic cascade effects, the intrinsic drivers of the disease and suggests an adaptive management strategy that might be applied by relevant conservation authorities.