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An analysis of trends in U.S. pharmaceutical spending is presented, including projections for drug expenditures in nonfederal hospital and clinic settings in 2015.Prescription drug expenditure data through September 2014 were obtained from the IMS Health National Sales Perspectives database and were analyzed descriptively. Other factors that may influence prescription spending in hospitals and clinics in 2015, including new drug approvals and patent expirations, were analyzed. Expenditure projections were based on a combination of quantitative and qualitative analyses and expert opinion.Total prescription sales for the 12 months ending September 30, 2014, were $360.7 billion, 12.2% higher than during the previous 12 months. With $6.6 billion in expenditures in the first 9 months of 2014, sofosbuvir topped the overall list of drugs based on sales, followed by aripiprazole and insulin glargine. Pharmaceutical spending by clinics and nonfederal hospitals rose by 13.3% and 4.0%, respectively. For the first 9 months of 2014, the top drugs based on expenditures were infliximab, pegfilgrastim, and epoetin alfa in clinics and infliximab, rituximab, and pegfilgrastim in hospitals. Specialty drugs continued to constitute an increasing portion of drug expenditures and will contribute to higher expenditures in 2015.Growth in U.S. prescription drug expenditures is expected to continue to increase in 2015. The projected increases in total drug expenditures are 7–9% across all settings, 12–14% in clinics, and 5–7% in hospitals. Health-system pharmacy leaders should carefully examine their own local drug utilization patterns to determine their own organization’s anticipated spending in 2015.