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Malignant catarrhal fever (MCF) is a highly lethal viral disease of cattle that poses a persistent threat to livestock production in wildlife-livestock interface areas of Southern Africa. Despite its recognized clinical severity, the economic burden of the disease remains poorly quantified in South African production systems. This study assessed the long-term economic impact of malignant catarrhal fever on cattle production in Lephalale Municipality, Limpopo Province, South Africa, using a retrospective analysis covering the period from 2001 to 2021. The study combined confirmed case records, estimated mortalities, and region-specific production parameters to quantify both direct and indirect economic losses. Direct losses included mortality-related financial costs and the expenditure on treatment, while indirect losses encompassed reduced productivity, diminished milk yields, and associated declines in overall herd performance. The results show that MCF imposed substantial financial burdens on cattle producers, with mortality contributing to more than ninety percent of total losses. The total economic losses over the study period were substantial, amounting to approximately R 1.55 million, driven primarily by high mortality-related costs. Annual losses displayed considerable variability, reflecting the sporadic nature of the outbreaks and the fluctuations in the wildlife-livestock interactions. The spatial analysis revealed that most cases occur in wards situated adjacent to wildlife conservation areas, where cattle are exposed to virus-carrying wildebeest populations. Seasonal patterns indicated a higher disease occurrence during the spring and winter, aligning with established transmission dynamics. Although a gradual decline in both cases and associated losses was observed over the study period, episodic outbreaks continued to exert significant economic shocks on affected farming households. The findings reaffirm MCF as a persistent and high-impact constraint to cattle production in interface zones and highlight the need for improved surveillance, integrated land-use planning, and sustained investment in targeted disease control measures.