Pansteatitis was confirmed in sharptooth catfish, Clarias gariepinus (Burchell), from three main locations within the Kruger National Park (KNP); the Olifants River Gorge, Engelhard Dam on the Letaba River and from the Sabie River in the Sabiepoort. An increasing prevalence of pansteatitis was observed in catfish during repeated samplings from the Olifants Gorge from 2009 to 2011 and co-existence of old and recent lesions indicated on-going incitement of pansteatitis. Only a low prevalence of pansteatitis was observed in catfish sampled from the Olifants River upstream of the Gorge in the KNP and no pansteatitis was observed in catfish sampled from a rain-filled dam not connected to the Olifants River. Common to both the Olifants Gorge and the Sabiepoort is the damming of the rivers in Mozambique to form lakes Massingir and Corumana respectively. Anthropogenic activities resulting in potential pollution of the rivers differ greatly between these two catchments, providing argument against a primary pollution-related aetiology of the pansteatitis found at these two sites. Compared with other sites, analysis of stomach contents of catfish from the Olifants Gorge and the Sabiepoort strongly suggested that consumption of a predominantly fish diet was associated with the development of pansteatitis in these fish. In a farmed population of catfish used as positive control, development of pansteatitis could be ascribed to consumption of rancid fish waste from a trout slaughterhouse. In the Olifants Gorge, alien invasive silver carp, Hypophthalmychthys molitrix (Valenciennes), seasonally migrate upstream out of Lake Massingir to spawn. This schooling species is an obligate phytoplankton feeder with consequent high levels of adipose tissue n-3 polyunsaturated fatty acids. In the Olifants Gorge, at least, this may explain seasonal exposure to levels of polyunsaturated fats in the diets of catfish and crocodiles to which these animals are not adapted. The possible roles of diet, membrane lipid composition and metabolic rate of fish, sediment pollution and seasonal drop in environmental temperature in the pathogenesis of pansteatitis in the catfish are discussed. Further studies are needed to verify some of these speculations.