Morphine has traditionally been considered the first line agent for analgesia in hospitals; however, in the last few years there has been a shift towards the use of hydromorphone as a first line agent. We conducted a hospital population based observational study to evaluate the increasing use of hydromorphone over morphine in both medical and surgical populations. Additionally, we assessed the effect of this trend on three key outcomes, including adverse events, length of stay, and readmission rates. We evaluated data from the University Health Systems Consortium. Data from 38 hospitals from October 2010 to September 2013 was analyzed for patients treated with either hydromorphone or morphine. The use of morphine steadily decreased while use of hydromorphone increased in both medical and surgical groups. Rescue drugs were used more frequently in patients treated with hydromorphone in comparison to patients treated with morphine (p < 0.01). Patients receiving morphine tended to stay in the hospital for almost one day longer than patients receiving hydromorphone. However, 30-day all cause readmission rates were significantly higher in patients treated with hydromorphone (p < 0.01). Our study highlights that the choice of hydromorphone versus morphine may influence outcomes. There are implications related to resource utilization and these outcomes.