We examined initiation patterns among different birth cohorts of people who used prescription opioids and heroin because of historical differences in drug use availability. We examined data from a community-based study of persons who inject drugs (n = 483) in California and a general population survey from the National Survey on Drug Use and Health (n = 1264) and found that individuals born after 1980 were more likely than were individuals born before 1980 to initiate opioids through nonmedical use of prescription opioids than heroin.