The objective of this study was to assess variations in the occurrence of temporomandibular disorders (TMDs) and the risk of developing pain and function impairment of the temporomandibular complex in obstructive sleep apnea syndrome (OSAS) patients treated with either an oral appliance (mandibular advancement device) or continuous positive airway pressure (CPAP) in a 2-year follow-up study. In addition, we assessed the relationship between the mean mandibular protrusion and the frequency of wearing the appliance during follow-up with the occurrence of pain and function impairment of the temporomandibular complex. Fifty-one patients were randomized to oral appliance therapy and 52 patients to CPAP therapy. TMDs (diagnosed according to the Axis I Research Diagnostic Criteria for TMD), pain intensity and disability and mandibular function impairment were recorded at baseline, after 2 months, 1 year and 2 years of therapy. Only in the initial period of treatment the occurrence of pain-related TMDs was considerably higher (24%) in the oral appliance group compared to CPAP (6%). Oral appliance therapy furthermore resulted in more temporomandibular pain compared to CPAP (odds ratio 2.33, 95% confidence interval (1.22-4.43)). However, there were no limitations in mandibular function in both groups during the (entire) follow-up period. Although generally not serious and of transient nature, oral appliance therapy results in more pain-related TMDs in the initial period of use compared with CPAP therapy. Oral appliance therapy is associated with increased pain in the temporomandibular complex in the initial period of use. Because of the transient nature, this pain is not a reason to contra-indicate an oral appliance in OSAS patients. Moreover, TMDs and the risk of developing pain and function impairment of the temporomandibular complex appear limited with long-term oral appliance use.