Humans introduce many toxicants into the environment, the long-term and indirect effects of which are generally unknown. We investigated exposure to anticoagulant rodenticides and evaluated the association between notoedric mange, an ectoparasitic disease, and anticoagulant exposure in bobcats (Lynx rufus) and mountain lions (Puma concolor) in a fragmented urban landscape in southern California, USA. Beginning in 2002, an epizootic of notoedric mange, a disease previously reported only as isolated cases in wild felids, in 2 years reduced the annual survival rate of bobcats from 0.77 (5-yr average) to 0.28. Anticoagulants were present in 35 of 39 (90%) bobcats we tested, multiple compounds were present in 27 of these 35 (77%), and total toxicant load was positively associated with the use of developed areas by radiocollared animals. Mange-associated mortality in bobcats showed a strong association with anticoagulant exposure, as 19 of 19 (100%) bobcats that died with severe mange were also exposed to the toxicants, and for bobcats with anticoagulant residues >0.05 ppm, the association with mange was highly significant (χ2 = 10.36, P = 0.001). We speculate that concomitant elevated levels of rodenticide exposure may have increased the susceptibility of bobcats to advanced mange disease. Bobcats were locally extirpated from some isolated habitat patches and have been slow to recover. In 2004, 2 adult mountain lions died directly from anticoagulant toxicity, and both animals also had infestations of notoedric mange, although not as advanced as in the emaciated bobcats that died with severe disease. Two other mountain lions that died in intraspecific fights also exhibited exposure to 2–4 different anticoagulants. These results show that the effects of secondary poisoning on predators can be widespread, reach even the highest-level carnivores, and have both direct and possibly indirect effects on mortality. Further research is needed to investigate the lethal and sub-lethal effects of anticoagulants and other toxicants on wildlife in terrestrial environments.