Despite the potential deleterious impact on patient safety, environmental safety and health care expenditures, the extent of unused prescription medications in US households and reasons for nonuse remain unknown. To estimate the extent, type and cost of unused medications and the reasons for their nonuse among US households. A cross-sectional, observational two-phased study was conducted using a convenience sample in Southern California. A web-based survey (Phase I, n=238) at one health sciences institution and paper-based survey (Phase II, n=68) at planned drug take-back events at three community pharmacies were conducted. The extent, type, and cost of unused medications and the reasons for their nonuse were collected. Approximately 2 of 3 prescription medications were reported unused; disease/condition improved (42.4%), forgetfulness (5.8%) and side effects (6.5%) were reasons cited for their nonuse. "Throwing medications in the trash" was found being the common method of disposal (63%). In phase I, pain medications (23.3%) and antibiotics (18%) were most commonly reported as unused, whereas in Phase II, 17% of medications for chronic conditions (hypertension, diabetes, cholesterol, heart disease) and 8.3% for mental health problems were commonly reported as unused. Phase II participants indicated pharmacy as a preferred location for drug disposal. The total estimated cost for unused medications was approximately $59,264.20 (average retail Rx price) to $152,014.89 (AWP) from both phases, borne largely by private health insurance. When extrapolated to a national level, it was approximately $2.4B for elderly taking five prescription medications to $5.4B for the 52% of US adults who take one prescription medication daily. Two out of three dispensed medications were unused, with national projected costs ranging from $2.4B to $5.4B. This wastage raises concerns about adherence, cost and safety; additionally, it points to the need for public awareness and policy to reduce wastage. Pharmacists can play an important role by educating patients both on appropriate medication use and disposal.