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In this prospective longitudinal clinical study with a matched-pair design, we evaluated the role of tumor necrosis factor-α (TNF-α) and its clinical relevance in patients with chronic low back pain.One hundred twenty patients with chronic low back pain were matched to a healthy control group. Patients and controls were prospectively followed for 6 months. At 4 fixed time points (day 0, day 10, day 20, and 6 mo) blood samples were taken and TNF-α levels compared in the 2 groups, and correlations with pain level and clinical function were analyzed.At the beginning and at all other time points, there was a significantly higher proportion of TNF-α positive participants in the patients group than in the control group. The proportion of TNF-α positive patients decreased during the first 10 days of a multidisciplinary therapy in the patient group, but after this initial period, TNF-α levels remained constantly high with no further change until the final follow-up. In the healthy control group, the proportion of participants with positive TNF-α levels remained constant throughout the entire period. No significant correlation between TNF-α levels and pain or clinical function was detected.TNF-α seems to have a significant role in patients with chronic low back pain. However, the pathophysiology of this process, the clinical relevance of TNF-α and, especially, its part in a potential therapy regimen in these patients need to be more closely examined and defined in additional studies.