Background: Pyogenic vertebral osteomyelitis represents a clinical challenge associated with significant morbidity and mortality. The aim of this study was to analyze potential risk factors for the in-hospital mortality of vertebral osteomyelitis (VO) patients. Methods: Based on the International Classification of Diseases, 10th Revision (ICD-10) codes for VO ("M46.2-", "M46.3-", and "M46.4-") data for total case numbers, secondary diagnoses, and numbers of in-hospital deaths were extracted from the Institute for the Hospital Remuneration System (InEK GmbH). Odds ratios (OR) for death were calculated for several secondary diseases and factors of interest. Results: Despite age, certain comorbidities were found to be strongly associated with increased mortality risk: Heart failure (OR = 2.80; 95% CI 2.45 to 3.20; p < 0.01), chronic kidney disease (OR = 1.83; 95% CI 1.57 to 2.13; p < 0.01), and diabetes with complications (OR = 1.86; 95% CI 1.46 to 2.38; p < 0.01). Among the complications, acute liver failure showed the highest risk for in-hospital mortality (OR = 42.41; 95% CI 23.47 to 76.62; p < 0.01). Additionally, stage III kidney failure (OR = 9.81; 95% CI 7.96 to 12.08; p < 0.01), sepsis (OR = 5.94; 95% CI 5.02 to 7.03; p < 0.01), acute respiratory failure (OR = 5.31; 95% CI 4.61 to 6.12; p < 0.01), and systemic inflammatory response syndrome (SIRS) (OR = 5.19; 95% CI 3.69 to 5.19; p < 0.01) were associated with in-hospital mortality. When analyzing the influence of pathogens, documented infection with Pseudomonas aeruginosa had the highest risk for mortality (OR = 2.74; 95% CI 2.07 to 3.63; p < 0.01), followed by Streptococci, Escherichia coli, and Staphylococcus aureus infections. Conclusions: An early assessment of individual patient risk factors may be beneficial in the care and treatment of VO to help reduce the risks of mortality. These findings emphasize the importance of closely monitoring VO patients with chronic organ diseases, early detection and treatment of sepsis, and tailored empirical antibiotic therapy. The identification of specific pathogens and antibiotic susceptibility testing should be prioritized to improve patient outcomes in this high-risk population.