Septic arthritis is an orthopedic emergency potentially causing irreversible joint damage. However, the predictive value of potential risk factors such as early postoperative laboratory parameters remains uncertain. We investigated risk factors for initial surgical treatment failure using data from 249 patients (194 knees, 55 shoulders) treated for acute septic arthritis between 2003 and 2018. Necessity for further surgical intervention was defined as primary outcome. Demographic data, medical history, initial and postoperative laboratory parameters, Charlson Comorbidity Index (CCI), and Kellgren and Lawrence classification were collected. Two scoring systems were developed as tools for failure risk estimation after initial surgical irrigation and debridement. More than one intervention was necessary in 26.1% of cases. Treatment failure occurred significantly more often for those with longer symptom duration (p = 0.003), higher CCI grades (p = 0.027), Kellgren-Lawrence grade IV (p = 0.013), shoulder arthroscopy (p = 0.010), positive bacterial culture results (p < 0.001), slow postoperative CRP decline until day three (p = 0.032) and five (p = 0.015), reduced WBC-decline (p = 0.008), and lower hemoglobin (p < 0.001). Scores for third and fifth postoperative day achieved AUCs of 0.80 and 0.85, respectively. This study identified risk factors for treatment failure in patients with septic arthritis, suggesting that early postoperative laboratory parameters can guide further treatment.