In a preliminary investigation of FDG-PET/CT for assessment of therapy response of pyogenic spine infection, it was concluded that activity confined to the margins of a destroyed or degenerated joint with bone-on-bone contact represents nonseptic inflammation, regardless of the intensity of uptake. Only activity in bone, soft tissue, or within the epidural space represents active infection. The purpose of this investigation was to assess the performance of these pattern-based interpretation criteria in a series of problem cases of proven or suspected spine infection. Eighty-two FDG-PET/CTs were done for initial diagnosis because other imaging failed to provide a definitive diagnosis and 147 FDG-PET/CTs were done to assess treatment responses. Pattern-based interpretations were compared with the clinical diagnosis based on bacterial cultures and outcomes after cessation or withholding of antibiotic therapy. Pattern-based interpretation criteria achieved a sensitivity and specificity of 98 and 100%, respectively, for initial diagnosis and a specificity of 100% for assessment of treatment response. The same data was analyzed using intensity of activity as the primary factor. Sensitivity and specificity using the intensity-based criteria were 93 and 68%, respectively, for initial diagnosis, and the specificity of a negative interpretation for therapy response was 55%. Differences from pattern-based criteria are highly significant. Pattern-based criteria perform well in problem cases with equivocal MR and for treatment response because they correctly eliminate activity from nonspecific inflammation associated with destroyed joints with bone-on-bone contact. Response occurs within a timeframe that is useful for managing antibiotic therapy.