Vaccinating African wild dogs (Lycaon pictus) against canine distemper virus (CDV) using live attenuated vaccines (LAV) has been controversial because of limitations in the vaccines' effectiveness and safety. However, CDV is a significant pathogen for African wild dogs, and CDV LAV are currently the only vaccines readily available on the African continent, making them a crucial tool for in situ conservation. There are few studies exploring immunogenicity of CDV LAV, and even less information pertaining to optimal vaccination protocols. This study reports the use of CDV LAV Vanguard^TM Plus 5/L in 16 African wild dogs from two sibling groups with initial inoculation at approximately 6–7 wk of age. The majority (81%, n = 13) of pups generated protective titers after initial vaccination. One pup died of CDV-suspected neurological disease within 17 d of initial vaccination. All remaining dogs received a second dose, and 100% of those achieved protective immunity (as per domestic dog reference values). Protective antibody titers were maintained throughout the sampling period of 284 and 373 d from the second vaccination. The risk of possible vaccine-induced disease cannot be excluded, but may be a sustainable risk compared with the protective potential of CDV LAV for African wild dogs.