Several prescription medications are approved to treat obesity, yet little is known about their use in the United States. Our objective was to describe recent trends and patterns of obesity reduction medication use in an insured US population. From among ~4.2 million persons enrolled in two Blue Cross and Blue Shield plans, we obtained all medical and pharmacy claims for 86,804 persons who took an obesity reduction medication anytime during 2002-2005. Overall, obesity reduction medication use decreased significantly over time from 1% in 2002 to 0.7% in 2005 (P for trend <0.001), which was most notable for the newer medications (orlistat and sibutramine). Few (range: 11-18%) used these medications longer than 3 months regardless of whether they were Federal Drug Administration (FDA)-approved for long-term use or not. More than half (57%) of obesity reduction medication users also took narcotics and 38% took antidepressants. Few sympathomimetic users had potential serious contraindications prior to medication initiation, including cardiovascular diseases (2.4%), schizophrenia (2.5%), and age >65 (1.2%). Despite the high prevalence of obesity, obesity reduction medication use was low and decreased significantly from 2002 through 2005. Prescribers of these agents should be aware of approved durations, potential contraindications, and consider screening for depression and substance abuse.