Understanding the effects of biodiversity loss on zoonotic disease is of pressing importance to both conservation science and public health. This paper provides experimental evidence of increased landscape-level disease risk following declines in large wildlife, using the case study of the rodent-borne zoonosis, bartonellosis, in East Africa. This pattern is driven not by changes in community composition or diversity of hosts, as frequently proposed in other systems, but by increases in abundance of susceptible hosts following large mammal declines. Given that rodent increases following large wildlife declines appear to be a widespread pattern, we suggest this relationship is likely to be general.