Purpose <p>The differential diagnosis of chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS) is important to avoid misdiagnosis and mistreatment. This study aimed to compare the laboratory and clinical findings of these two diseases.</p> Methods <p>Patients who presented with hypercapnic respiratory failure and were hospitalized for at least 5 days were included. The patients’ clinical findings and laboratory parameters at admission were compared. The STOP-Bang questionnaire and Berlin Sleep Questionnaire were used to evaluate risk of sleep apnea, and dyspnea was assessed with the modified Borg scale. Improvements in clinical and blood gas parameters during follow-up were also evaluated.</p> Results <p>Patients with OHS had higher diastolic blood pressure, STOP-Bang scores, frequency of high apnea risk according to the Berlin Sleep Questionnaire, and frequency of pulmonary hypertension (PH) when compared with the COPD group (<i>p</i> = 0.01, &lt; 0.001, &lt; 0.001, and &lt; 0.001, respectively). Waist circumference, triglyceride level, and frequency of metabolic syndrome were also higher in the OHS group (<i>p</i> &lt; 0.001 for all). High Berlin Sleep Questionnaire score and body mass index (BMI) were significant discriminators for OHS, while the presence of bronchial obstruction was a discriminator for COPD. Evaluation of these three parameters together enabled differential diagnosis in 85% of cases.</p> Conclusion <p>Patients with OHS who present with hypercapnic respiratory failure may be misdiagnosed as having COPD because of the similar clinical pictures. Clinicians should consider OHS in patients with high BMI, increased risk of sleep apnea, and no obstructive findings on physical examination.</p>