Background: Topical immunomodulators (TI)-including corticosteroids, calcineurin inhibitors, and vitamin D analogues-are commonly prescribed in multiple specialties, but cost comparisons are lacking. Objective: To evaluate differences in costs of TI across specialties and determine associated variables. Methods: A cross-sectional study was performed using the Centers for Medicare & Medicaid Services 2008 and 2010 Prescription Drug Public Use Profiles, which contain 100% of drug claims made by Medicare beneficiaries. Results: Branded drugs cost an average of $174.02 more than generics per 30-day supply (P < .001). Differences in health insurance benefit phase, drug choice, brand name, and coverage type were the greatest determinants of patient cost (P < . 001). Prescriptions for low-, medium-, and high-potency TI from specialists (mostly dermatologists) cost more than those from family medicine, internal medicine, and psychiatry/neurology physicians; total costs of a 30-day supply from a specialist differed from family and internal medicine physicians by $7.36-$14.57, and patient costs were higher for specialists by $1.69-$3.16 (P < . 01). Brand names were prescribed 8% of the time by specialists and 1.4%-3.1% by nonspecialists. Limitations: We were unable to adjust for some confounders of cost, such as medication weight or treated body area, and the data does not reflect previous treatment failures or use by non-Medicare patients. Conclusion: The costs of TIs prescribed by specialists (primarily dermatologists) are higher than those prescribed by primary care physicians and could be reduced by choosing more generics within the respective potency classes.