Background/Objectives: Conservative treatment of patients with pyogenic spinal infection is a well-established therapy. Nevertheless, treatment failure is often seen despite adequate antibiotic therapy. The aim of this study was to evaluate predictors of treatment failure facilitating individualized, patient-specific therapy and thus increasing the success of therapy. Methods: We retrospectively evaluated medical data and radiological findings of patients who were admitted between 2012 and 2023. Treatment failure and readmission were analyzed. Vertebral body lesions and spinal deformity were assessed at admission and follow-up. Patient comorbidities were assessed using the Charlson Comorbidity Index (CCI). Each patient underwent CT and MR imaging of the affected part of the spine. During follow-up, a new CT scan was performed to show the extent of the spinal lesion. Results: A total of 245 patients with a mean age of 65.4 years were included in the final analysis. The gender distribution included 164 (67%) male and 81 (33%) female patients. The mean follow-up time was 46 months (range 5-96 months). Among 245 patients, 86 (35.1%) received conservative therapy, and treatment failure was observed in 34 (40%) of them, compared to 6 (4%) in the surgical group (p < 0.001). The progression of vertebral body lesions was identified as a potential reason for treatment failure in these patients. Radiological follow-up data revealed an average of 32% destruction compared to the initial CT scan. A significant association was observed between treatment failure and age (p = 0.007, CI 95%: 97.8-100%), cervical discitis (p = 0.018, CI 95%: 97.3-100%) and high CCI scores (p = 0.001, CI 95%: 98.3-99.5%). Conclusions: In our study, we were able to show that factors such as age, position of the cervical spine and a high CC index were significantly associated with treatment failure. This was due to increasing bone destruction. Early surgical treatment may prevent the progression of osteolysis and long-term complications such as persistent back pain and the need for subsequent complex surgery. These predictors may also help guide individualized, patient-specific therapy for conservatively treated patients, thereby improving treatment outcomes.