In North America, dense populations of white-tailed deer (Odocoileus virginianus) in suburbs, cities and towns have stimulated a search for new population-management tools. Most research on deer contraception has focused on the safety and efficacy of immunocontraceptive vaccines, but few studies have examined population-level effects. We report here results from two long-term studies of population effects of the porcine zona pellucida (PZP) immunocontraceptive vaccine, at the National Institute of Standards and Technology (NIST), Gaithersburg, Maryland, USA, and at Fire Island National Seashore (FIIS), New York, USA. Annual population change at NIST was strongly correlated with population fertility (rP = 0.82, P = 0.001); when population fertility at NIST dropped below 0.40 fawns per female, the population declined. Contraceptive treatments at NIST were associated with a 27% decline in population between 1997 and 2002, and fluctuated thereafter with the effectiveness of contraceptive treatments. In the most intensively treated segment of FIIS, deer population density declined by ~58% between 1997 and 2006. These studies demonstrate that, in principle, contraception can significantly reduce population size. Its usefulness as a management tool will depend on vaccine effectiveness, accessibility of deer for treatment, and site-specific birth, death, immigration, and emigration rates.