Background: Long-term oxygen treatment (LTOT) is very important, especially in patients with severe chronic obstructive pulmonary disease (COPD), but its efficacy is closely related to patient compliance. Objectives: The aim of the present study was to investigate the compliance of patients under LTOT in the Prefecture of Ioannina (north-western Greece) and to identify factors that might be involved. Methods: The study included 249 patients treated with LTOT during a 1-year period. They were visited at home by the investigating staff (a chest specialist and a primary care nurse). Compliance to therapy was defined by the daily use of the O2 concentrator (in hours). Patients underwent pulse oximetry, basic spirometry, and trial inhalation of bronchodilators. Results: Only 67 patients (26.9%) complied with therapy, while the daily concentrator use lasted 9.7 ± 6.09 h. SaO2, FEV1 and FVC were negatively correlated to patient compliance. No significant differences concerning LTOT compliance were noted between men and women, urban and rural population, and between smokers, ex-smokers and non-smokers. A chest physician recommended LTOT for the majority of patients (86.3%), while COPD was the main reason for LTOT prescription (74.7%). Nevertheless, compliance to LTOT was not significantly higher when prescribed by a respiratory physician. No specific medical instructions and information was recorded for the majority of the study patients treated with LTOT. Conclusions: Our results suggest that an organized home care program establishing the relative guidelines is necessary for substantial improvement in patient compliance to LTOT in Greece.