Data on canine distemper virus (CDV) vaccination were collected on 812 large felids (351 tigers, Panthera tigris; 220 lions, Panthera leo; 143 snow leopards, Panthera uncia; 50 leopards, Panthera pardus; and 48 jaguars, Panthera onca) from 48 institutions to assess vaccine use and safety. The documented individual vaccination events with multiple products numbered 2,846. Canarypox-vectored CDV vaccines were the most commonly used vaccines (96.3% of all vaccinations) and the Purevax^® Ferret Distemper (PFD) vaccine was the most commonly used canarypox-vectored vaccine (91.0% of all vaccinations). Modified live virus (MLV) CDV vaccines were used for 3.7% of all vaccinations, and only in tigers, lions, and snow leopards. Adverse effects were reported after 0.5% (13 of 2,740) of the canarypox-vectored vaccinations and after 2.9% (3 of 104) of the MLV CDV vaccinations. This low complication rate suggests large felids may not be as sensitive to adverse effects of MLV CDV vaccines as other exotic carnivores. Serological data were available from 159 individuals (69 tigers, 31 lions, 31 snow leopards, 22 jaguars, and 6 Amur leopards, Panthera pardus orientalis) vaccinated with the PFD vaccine, and 66.0% of vaccinates seroconverted (defined as acquiring a titer ≥1: 24) at some point postvaccination: 24.3% after one vaccination, 55.8% after two vaccinations, 54.3% after three vaccinations, and 79.2% after four or more vaccinations. Among animals exhibiting seroconversion after the initial PFD vaccinations, 88.9% still had titers ≥12 mo and ≥24 mo after the last vaccination, and 87.5% had titers ≥1: 24 at ≥36 mo after the last vaccination. The study was unable to assess fully the safety of vaccination with either canarypox-vectored or MLV CDV vaccines during gestation because of the small number of animals vaccinated while pregnant (n = 6, all vaccinated with PFD).