Objectives: The aim of this randomized placebo-controlled trail was to compare the effects of an objectively titrated mandibular advancement device (MAD) with those of nasal continuous positive airway pressure (nCPAP) and an intraoral placebo device on symptoms of psychological distress in OSA patients. Materials and methods: In a parallel design, 64 mild/moderate OSA patients (52.0 ± 9.6 years) were randomly assigned to an objectively titrated MAD, nCPAP, or an intraoral placebo appliance. All patients filled out the Symptom Checklist-90-Revised twice: one before treatment and one after 6 months of treatment. The Symptom Checklist-90-Revised is a multidimensional symptom inventory designed to measure symptomatic psychological distress over the past week. Linear mixed model analyses were performed to study differences between the therapy groups for the different dimensions of the Symptom Checklist-90-Revised over time. Results: The MAD group showed significant improvements over time in the dimensions “somatization,” “insufficiency of thinking and acting,” “agoraphobia,” “anxiety,” “sleeping problems,” and “global severity index” (F = 4.14–16.73, P = 0.048–0.000). These improvements in symptoms of psychological distress were, however, not significantly different from those observed in the nCPAP and placebo groups (P = 0.374–0.953). Conclusion: There is no significant difference between MAD, nCPAP, and an intraoral placebo appliance in their beneficial effects on symptoms of psychological distress. Clinical relevance: The improvement in psychological distress symptoms in mild/moderate OSA patients under MAD or nCPAP treatment may be explained by a placebo effect.