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 mixture was 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 a burst release of CH in the early stage of the dissolution process though a sustained release appeared in the late stage. The in vivo burst release of CH would lead to unexpected side effect. The original retainer was modified by coating with hydrophilic polymers or washing with buffered solutions to obtain the coated or washed retainer. The coated retainer still showed a burst release while the washed retainer showed an optimal sustained release. Many CH microparticles existed on the surface of original retainers according to the scanning electron microscopic image so that the burst release was unavoidable. The hydrophilic polymer coating method did not change the release profile because the polymer was also rapidly dissolved. However, most of the surface CH can be eliminated by washing so that the burst release dissappeared in the washed retainer. Furthermore, the simulated CH concentration-time profiles in the circulation of humans of the washed retainer showed the stable and appropriate drug levels for more than 3 days. Wearable personalized 3D printed drug-loaded orthodontic retainers are a promising drug-device for sustained release of drugs.