OBJECTIVES:  To investigate health care use and expenditures in specialty medication users compared with traditional medication users. METHODS:  This was a retrospective cohort study of US adults aged 18 or older using Medical Expenditure Panel Survey (MEPS) data from 2000 through 2013. MEPS respondents aged 18 or older who used any specialty medications were considered specialty medication users (SMUs). Individuals who used pharmaceuticals other than specialty medications were considered traditional medication users (TMUs). Outcomes of health care use included the number of prescription medications as well as the annual number of emergency department visits, hospitalizations, office-based visits, and hospital outpatient visits. Outcomes of health care expenditures included total health care expenses, total prescription medication expenses, out-of-pocket (OOP) expenses for prescription medications as well as spending on emergency department visits, hospitalization, office-based visits, and hospital outpatient visits. For outcomes of health care use, a negative binomial model (or a zero-inflated negative binomial regression model for the outcomes with excessive zeros) was employed. To analyze the outcomes of health care spending, a generalized linear model (GLM) with a log link function and gamma distributed errors (or a two-part model for zero-inflated expenditure data) was used. RESULTS:  After controlling for the various covariates, SMUs used about 65% fewer prescription medications (incidence rate ratio [IRR] = 0.35, 95% CI = 0.18-0.67) and had 68% fewer hospital outpatient visits (IRR = 0.32, 95% CI = 0.16-0.68) compared with TMUs. However, SMUs spent about $3,600 more on prescription medications while their OOP medication spending was about $100 less than TMUs. CONCLUSIONS:  Compared with TMUs, SMUs used less prescription medications and had less hospital outpatient visits. Spending on prescription medications was higher by SMUs than TMUs, unlike OOP spending.