The aim of the present study was to determine the effect of middle and long-term positive airway pressure (CPAP) treatment on the health-related quality of life in patients with obstructive sleep apnea. We prospectively studied two groups of patients with this disease; a group of 42 patients (33 men and 9 women) with a mean age of 55.2 +/- 7.4 years and a body mass index of 33.5 +/- 6.4 kg/m2 treated with CPAP for 6-months, and another group of 42 patients (34 men and 8 women) with a mean age of 54.4 +/- 10.5 years and a body mass index of 33.2 +/- 4.0 kg/m2 treated with CPAP for 18-months. The health related quality of life was assessed by administering a Medical Outcomes Study Short Form-36 (SF-36) questionnaire before and after CPAP therapy. Patients treated with CPAP for 6 months only improved significantly in the vitality dimension and this change was clinically relevant (standard error of the measurement = 1.43 SEmeas). In contrast, those treated with CPAP for a long period (18-month) showed statistically significant improvement at post-treatment in five SF-36 dimensions: physical functioning (P < 0.001), role physical (P < 0.01), social functioning (P < 0.01), vitality (P < 0.001), and general health perception (P < 0.001). In four of these dimensions the improvement was clinically relevant: role physical (1.16 SEmeas), social functioning (1.35 SEmeas), vitality (1.35 SEmeas), and general health perception (2.05 SEmeas). Using two different global rating of change (independent measures or anchors), the minimal change important difference for patients treated with CPAP for 6 months ranged from 20.7 to 24.2 points on the vitality dimension; and for patients with CPAP for 18-months it ranged from 2.5 to 7.5 points on the physical role, 5.5-6.6 points on social functioning, 7.5-8.7 on vitality, and 13.5-15.5 on general health perception dimension. We conclude that health-related quality of life of obstructive sleep apnea patients improves with long term CPAP treatment and these changes are clinically relevant in several health dimensions.