OBJECTIVES: Besides the influence of economic factors, prescribing patterns, and market dynamics, decisions to withdraw products from the market are driven by concerns over safety. This study evaluated new molecular entities (NMEs) approved by the FDA in the period 1980-2009 that were withdrawn from the market for safety reasons.   METHODS: Data were obtained from the FDA and the US Federal Register. Descriptive analyses were used to classify product discontinuations by therapeutic category, year, and reason for discontinuation.   RESULTS: There were 740 NMEs approved by the FDA during the study period. As of December 1, 2010, the number of drugs discontinued was 118 (15.9%). Safety was the reason for withdrawing 27 (3.6%) drugs from the market. Therapeutic categories with the most safety withdrawals as a percentage of approvals in the 1980s were respiratory (28.6%), musculo-skeletal (23.1%), and nervous system (7.4%). During the 1990s, classes with the most safety withdrawals as a percentage of approvals were musculo-skeletal (18.8%), alimentary tract and metabolism (12.0%), and blood and blood forming organs (7.7%). Therapeutic categories affected by safety withdrawals as a percentage of approvals in the 2000s were musculo-skeletal (20.0%), alimentary tract and metabolism (4.2%), and antineoplastic and immunomodulating agents (3.2%). Major problems that spurred safety withdrawal were hepatic toxicity, severe cardiovascular effects, and gastrointestinal issues. Average time from approval to safety withdrawal was 5.9 (SD = 5.0) years, with a range of 0.3-18.2 years, and a 95% CI of 4.0-7.8 years. CONCLUSIONS: Approximately one in seven NMEs approved in the period 1980-2009 was discontinued from the market. Less than one-quarter of the discontinuations were attributed to safety reasons. Products remained in the market for an average of six years before safety withdrawal. An ongoing evaluation of new drugs through their product life cycle is important to determine their long-term safety and value to society.