This study prospectively followed 161,318 women who were discharged after childbirth between January 2007 and August 2014 to assess the risk of serious opioid-related events after vaginal and cesarean births. Both vaginal births (59%) and cesarean births (91%) involved one or more filled opioid prescription. Serious opioid-related events were 1.4- and 3.6-times more likely to occur among women filling one or two prescriptions compared to women who did not fill any opioid prescription after childbirth. Reducing opioid prescribing after childbirth may decrease the incidence of future serious opioid-related events.