Compared with nonindigenous people, indigenous people in first-world countries have experienced much higher rates of many vaccine preventable diseases. This systematic review of published scientific literature, government reports, and immunization guidelines from Australia, Canada, New Zealand, and the United States compares pre- and postvaccination disease rates and vaccination policy for indigenous people in these four countries. Nationally funded universal vaccination programs are clearly the most effective way of reducing disease in indigenous populations. Most successful have been programs for viral diseases in which strain variations are not important and herd immunity is high, such as measles and hepatitis B. For bacterial infections, strain variations (pneumococcal disease), heavy nasopharyngeal colonization of young infants (pneumococcal and Haemophilus influenzae type b disease), low vaccine effectiveness in adults with a high prevalence of risk factors (polysaccharide pneumococcal vaccine), and waning immunity (pertussis) have been associated with continuing or widening disparities between indigenous and nonindigenous populations. However, universal vaccination programs are not always possible. Geographic targeting of all persons in certain regions with high disease rates has been successful, as has targeting of indigenous populations in regions where they constitute larger proportions of the population. In national programs targeting only indigenous people, it has been difficult to achieve high coverage, particularly in urban areas. Innovative program approaches are particularly needed in these situations.