Background. Overlap syndrome (OS) describes the association of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) in a single individual. Subjects with OS have increased cardiovascular mortality which is presumed to be inflammation-mediated. As a clinical biomarker, an increased neutrophil count correlates with the severity of coronary artery stenosis. Objectives. As little is known about the role of neutrophils in the underlying inflammatory mechanisms in OS, we aimed to assess the percentage of peripheral neutrophils (PPN) in OS vs in COPD alone. Material and methods. A cross-sectional study of patients with COPD and severe comorbidities, as defined by a Care Assessment Need score over 95, were seen in the Pulmonary Tele-Health Clinic at the Salem Veteran Affairs Medical Center, USA, over a 1-year period. Demographic and polysomnographic data, FEV1 and the Charlson Comorbidity Index (CCI) were extracted from the Electronic Medical Records. Obstructive sleep apnea was defined according to the American Academy of Sleep Medicine (AASM) guidelines. Serum inflammatory markers (PPN, CRP, fibrinogen and procalcitonin) were obtained after the Tele-Health appointment. Results. Out of the 38 subjects with COPD, 17 (44%) had OS. Compliance with continuous positive airway pressure therapy (CPAP) was excellent in 7 OS subjects (41%). There was a significant difference in the PPN of subjects with OS vs COPD alone, regardless of whether they were compliant (p = 0.03) with the CPAP therapy or not (p = 0.005). No differences in the severity of COPD, baseline comorbidity, smoking, or inflammatory markers were found between the OS and COPD-only subjects. Body mass index (BMI), COPD severity, smoking, and home oxygen therapy (HOT) use were not associated with PPN (p > 0.2). Conclusions. Overlap syndrome subjects have higher PPN than those with COPD alone, regardless of their CPAP compliance. Our results could be used to motivate OS subjects to improve their lifestyles and to comply with drug therapies aimed at reducing cardiovascular disease (CVD).