Severe neurological deficit (SND) is a rare but major complication of pyogenic vertebral osteomyelitis (PVO). We aimed to determine the risk factors and the variables associated with clinical improvement for SND during PVO.This case-control study included patients without PVO-associated SND enrolled in a prospective randomized antibiotic duration study, and patients with PVO-associated SND managed in 8 French referral centers. Risk factors for SND were determined by logistic regression.Ninety-seven patients with PVO-associated SND cases, and 297 controls were included. Risk factors for SND were epidural abscess [adjusted odds ratio, aOR 8.9 (3.8-21)], cervical [aOR 8.2 (2.8-24)], and/or thoracic involvement [aOR 14.8 (5.6-39)], Staphylococcus aureus PVO [aOR 2.5 (1.1-5.3)], and C-reactive protein (CRP) >150 mg/L [aOR 4.1 (1.9-9)]. Among the 81 patients with PVO-associated SND who were evaluated at 3 months, 62% had a favorable outcome, defined as a modified Rankin score ≤ 3. No factor was found significantly associated with good outcome, whereas high Charlson index [adjusted Hazard Ratio (aHR) 0.3 (0.1-0.9)], low American Spinal Injury Association (ASIA) impairment scale at diagnosis [aHR 0.4 (0.2-0.9)], and thoracic spinal cord compression [aHR 0.2 (0.08-0.5)] were associated with poor outcome. Duration of antibiotic treatment was not associated with functional outcome.SND is more common in cervical, thoracic, and S. aureus PVO, in the presence of epidural abscess, and when CRP >150 mg/L. Although neurological deterioration occurs in 30% of patients in early follow-up, the functional outcome is quite favorable in most cases after 3 months. The precise impact of optimal surgery and/or corticosteroids therapy must be specified by further studies.