Secondhand smoke (SHS) exposure causes heart disease and lung cancer in nonsmoking adults and several health conditions in children. Only completely eliminating smoking in indoor spaces fully protects nonsmokers from SHS. State and local laws can provide this protection in enclosed workplaces and public places by completely eliminating smoking in these settings. CDC considers a smoke-free law to be comprehensive if it prohibits smoking in all indoor areas of private workplaces, restaurants, and bars, with no exceptions. In response to growing evidence on the health effects of SHS, communities and states have increasingly adopted comprehensive smoke-free (CSF) laws in recent years. To assess trends in protecting the population from SHS exposure, CDC and the American Nonsmokers' Rights Foundation (ANRF) compared coverage by local or state CSF laws in the 50 largest U.S. cities as of December 31, 2000, and October 5, 2012. The analysis focused on smoking restrictions in the 50 largest cities because these cities represent an important indicator of nationwide trends in local and state policy and because they are home to an estimated 47 million persons, or nearly 15% of the U.S. population. The analysis found that the number of these cities covered by local and/or state CSF laws increased from one city (2%) in 2000 to 30 cities (60%) in 2012. A total of 20 cities (40%) were not covered by a CSF law at either the local or state level in 2012, although 14 of these cities had 100% smoke-free provisions in place at the local or state level in at least one of the three settings considered. The results of this analysis indicate that substantial progress has been achieved during 2000-2012 in implementing CSF laws in the 50 largest U.S. cities. However, gaps in coverage, especially in the southern United States and in states with laws that preempt local smoking restrictions, are contributing to disparities in SHS protections.