Hospitals now have the responsibility to implement strategies to prevent adverse outcomes after discharge. This systematic review addressed the effectiveness of hospital-initiated care transition strategies aimed at preventing clinical adverse events (AEs), emergency department (ED) visits, and readmissions after discharge in general medical patients. MEDLINE, CINAHL, EMBASE, and Cochrane Database of Clinical Trials (January 1990 to September 2012) were searched, and 47 controlled studies of fair methodological quality were identified. Forty-six studies reported readmission rates, 26 reported ED visit rates, and 9 reported AE rates. A “bridging” strategy (incorporating both predischarge and postdischarge interventions) with a dedicated transition provider reduced readmission or ED visit rates in 10 studies, but the overall strength of evidence for this strategy was low. Because of scant evidence, no conclusions could be reached on methods to prevent postdischarge AEs. Most studies did not report intervention context, implementation, or cost. The strategies hospitals should implement to improve patient safety at hospital discharge remain unclear.