Background: Although osteoarthritis (OA) has predominantly been considered a noninflammatory degenerative arthropathy, there is growing evidence that various inflammatory and immunological processes might contribute to the onset, progression, and burden of the disease.Objective: The purpose of the present investigation was to study the systemic inflammatory and stress responses and the innate response mediated by neutrophils in OA patients. Method: A group of patients diagnosed with primary OA according to the American College of Rheumatology criteria and a control group of age-matched healthy volunteers were enrolled in the study. Serum inflammatory cytokine levels (IL-1β, TNF-α, IL-8, IL-6, IL-10, and TGF-β) were evaluated using the Bio-Plex Luminex system. Circulating neuroendocrine-stress biomarkers, such as cortisol and extracellular 72 kDa heat shock protein (eHsp72), were measured by ELISA. The phagocytic and microbicide capacities of circulating neutrophils were evaluated by flow cytometry. All parameters were determined in all volunteers. Results: The OA patients showed an inflammatory state accompanied by an altered stress response. This was manifested in high circulating levels of the inflammatory cytokines IL-1β, TNF-α, IL-8, IL-6, and TGF-β and the stress protein eHsp72. There were also decreased systemic levels of cortisol, and a reduction in neutrophil phagocytic and microbicidal capacities. Conclusion: An immune-neuroendocrine dysregulation affecting both systemic inflammatory and stress mediators and the function of innate immune cells underlies OA. This reflects an altered feedback between the innate/inflammatory and stress responses in this pathology.