Most large carnivore species are in global decline. Conflicts with people, particularly over depredation on small and large livestock, is one of the major causes of this decline. Along tropical deforestation frontiers, large felids often shift from natural to livestock prey because of their increased proximity to human agriculture, thus increasing the likelihood of conflicts with humans. On the basis of data from 236 cattle ranches, we describe levels of depredation by jaguars Panthera onca and pumas Puma concolor on bovine herd stocks and examine the effects of both landscape structure and cattle management on the spatial patterns and levels of predation in a highly fragmented forest landscape of southern Brazilian Amazonia. Generalized linear models showed that landscape variables, including proportion of forest area remaining and distance to the nearest riparian forest corridor, were key positive and negative determinants of predation events, respectively. We detected clear peaks of depredation during the peak calving period at the end of the dry season. Bovine herd size and proportion of forest area had positive effects on predation rates in 60 cattle ranches investigated in more detail. On the other hand, distance from the nearest riparian forest corridor was negatively correlated with the number of cattle predated. The mean proportion of cattle lost to large felids in 24 months for the region varied according to the herd class size (<500: 0.82%; 500–1500: 1.24%; >1500: 0.26%) but was never greater than 1.24%. The highest annual monetary costs were detected in large cattle ranches (>1500 head of cattle), reaching US$ 885.40. Patterns of depredation can be explained by a combination of landscape and livestock management variables such as proportion of forest area, distance to the nearest riparian corridor, annual calving peak and bovine herd size.