Persistent low back pain after spinal stabilization with instrumentation remains a frequent and clinically demanding condition. In many cases, pain persists despite pharmacological therapy and rehabilitation, limiting quality of life. Among emerging non-surgical options, oxygen–ozone (O₂–O₃) therapy has been proposed for its analgesic, anti-inflammatory, and neuromodulatory properties. This study aims to evaluate the clinical effectiveness of computed tomography (CT)-guided infiltrative O₂–O₃ treatment in patients with chronic low back pain following spinal fusion and to compare outcomes with those of standard pharmacological therapy within structured rehabilitative care. This observational retrospective study included 168 adult patients with low back pain persisting for more than six months after posterior spinal fusion with screws and plates. Group A (n = 72) received CT-guided paravertebral infiltrations of an O₂–O₃ gas mixture at 20 μg/mL, followed by individualized physiotherapy. Group B (n = 96) received a combination of pharmacological agents (oxycodone/ paracetamol and pregabalin) alongside the same rehabilitative program. Clinical evaluation was performed at baseline (T0), 1 month (T1), and 6 months (T2) using the Visual Analog Scale (VAS) and the modified McNab scale. Group A showed a significant mean VAS reduction (>3 points) already at T1, with benefits maintained at T2. Functional recovery was rated as “good” or “excellent” in approximately 60% of cases. In contrast, Group B exhibited a transient response at T1, with VAS scores returning close to baseline at T2. Intergroup differences in both pain reduction and functional improvement were statistically significant (p < 0.001). CT-guided O₂–O₃ infiltrative therapy, integrated with physiotherapy, was associated with better clinical outcomes compared to pharmacological treatment alone in patients with persistent low back pain after spinal fusion. These findings suggest a potential role for O₂–O₃ therapy within a multimodal treatment approach for selected post-surgical patients.

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