Mandibular advancement splints (MAS) are a recognized therapeutic option in the treatment of obstructive sleep apnea (OSA). This study aimed to investigate side effects and possible changes in the dentofacial complex associated with long term use of MAS. Methods: The sample included 64 patients with OSA who had been using MAS on average for 25.1 ± 11.8 months (range, 10.7-64.5 months). A specifically designed questionnaire was used to investigate the patients’ self-assessment of the side effects of wearing MAS; cephalometric analyses and dental cast measurements were conducted to identify objectively dental and skeletal changes caused by MAS over time. Results: The most commonly reported side effects were jaw discomfort, tooth tenderness, excessive salivation, and dry mouth. Subjectively, snoring improved in 56 patients (88%), and daytime sleepiness (Epworth sleepiness scale) scores significantly decreased from pretreatment to follow-up (11.4-7.1, P <.001). Small subjective occlusal changes were experienced by 8 patients (12.5%). Reductions in overbite (-0.3 ± 0.08 mm, P <.01) and overjet (-0.2 ± 0.06 mm, P <.05) were found, and cephalometric analysis showed statistically significant but clinically insignificant changes limited to anterior movement of the mandibular incisors (0.5 ± 0.12 mm, P <.001). Conclusions: Side effects of MAS use over long periods are common but mild and well tolerated by most patients, and dentofacial changes are negligible.