Objectives This study examined trends in prescription drug abuse and dependence (sedatives, tranquilizers, opioids, and stimulants), co-occurrence with other substance use disorders and substance abuse treatment utilization among those with diagnoses of prescription drug abuse and dependence in two large, nationally representative, independent samples of adults in the United States in 1991–1992 and 2001–2002. Methods Two nationally representative cross-sectional samples of civilian non-institutionalized adults 18 years or older in the United States, of which 52% were women. Data were collected from structured diagnostic interviews using the NIAAA Alcohol Use Disorder and Associated Disabilities Interview Schedule: Diagnostic and Statistical Manual version IV (DSM-IV). National prevalence estimates were derived from the 1991–1992 National Longitudinal Alcohol Epidemiologic Survey (n = 42,862) and the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (n = 43,093). Results The past-year prevalence of prescription sedative abuse, sedative dependence, opioid abuse, and opioid dependence increased from 1991–1992 to 2001–2002. The majority of individuals with past-year sedative (56.8%), tranquilizer (89.0%), stimulant (67.9%) and opioid (74.2%) use disorders also met DSM-IV criteria for an additional past-year substance use disorder. The co-occurrence of several forms of prescription drug use disorders and other substance use disorders increased from 1991–1992 to 2001–2002. A minority of individuals with past-year prescription drug abuse and approximately one-half of those with past-year prescription drug dependence utilized substance abuse treatment. Conclusions The findings reinforce the importance of continued national monitoring based on the increases in prescription drug abuse and dependence, high co-occurrence with other substance use disorders, and underutilization of substance abuse treatment services.