Orthodontic retainers are wearable customizable medical devices for dental protection or alignment. Here, clonidine hydrochloride (CH)-loaded wearable personalized 3D printed orthodontic retainers were studied for local sustained-release of drugs. CH powders were mixed with PEG 4000, Tween 80, poly(lactic acid), and polycaprolactone.The mixturewas hot-melt extruded to form a filament that was 3D printed to a customizable original orthodontic retainer with the fused deposition modeling (FDM) method. The original retainer showed aburst release of CH in the early stage of thedissolutionprocess though asustained release appearedin the late stage. Thein vivo burst release of CH would lead to unexpected side effect. The original retainer was modified by coating with hydrophilicpolymers or washing with buffered solutions to obtain the coated or washed retainer. The coated retainer still showed a burst releasewhile the washed retainer showed an optimalsustained release. ManyCH microparticles existed on the surface of original retainers according to the scanning electron microscopic image so that the burst releasewas unavoidable. The hydrophilic polymer coating method did not change the releaseprofile because the polymer was also rapidly dissolved. However, most ofthe surface CH can be eliminated by washing so that the burst release dissappearedin the washed retainer. Furthermore, the simulated CH concentration-time profiles in the circulation of humans of thewashed retainer showed the stable and appropriate drug levels for more than 3days. Wearable personalized 3D printed drug-loaded orthodontic retainers are a promising drug-device for sustained release of drugs.