There is a direct connection between drug and substance use and HIV transmission. Injecting drug use is estimated to be directly responsible for over 5% of HIV infections worldwide. The use of recreational drugs, including alcohol, is also associated with unsafe sexual activity that can in turn result in HIV infection. Worldwide, men are more likely than women to use such substances.

Of the estimated six to seven million persons around the world who inject drugs, four-fifths are men. Male drug injectors are more likely than women to have non-injecting partners, are more likely to share needles than women, and tend to be the first to use shared injecting equipment. In a major thirteen-city study, the majority of injecting drug users with regular sex partners reported never using condoms.

Men and boys also use substances that are not injected at higher rates than women and girls. For many men, using alcohol and other substances helps prove manhood and helps them fit in with their peers. Young people interviewed in a recent study in Brazil said they sometimes smoked marijuana or drank before going to parties to give them the "courage to find a partner". Young men interviewed in Thailand said they frequently drink before paying for sex with women bar workers. In a study in the U.S., 31% of young men said they "are always or sometimes high on alcohol or drugs during sex". While the links between the use of "party drugs" such as Ecstasy and sexual risk are far from clear, such drugs can impair judgement in ways that make sexual risk-taking more likely.

Programmes aimed at preventing HIV transmission to and from men through sex and drug use -- including education and harm-reduction programmes for injecting drug users -- exist in many countries, often without the approval of local or state governments. The most effective programmes not only hand out sterilization materials to clean needles and syringes, or offer clean needles when the law allows them to so, but also take into account how boys and men view substance use and their specific motivations for drinking and taking drugs.