Objective: To study the additional use of topical antibiotic-loaded calcium sulfate pellets in difficult-to-treat cases of temporal bone infections. Patients: Four patients with advanced and pretreated temporal bone disease. Intervention: Application of topical antibiotic-loaded calcium sulfate pellets following surgical debridement in infections of the temporal bone. Main Outcome Measures: Reinfection- and revision-free follow-up analysis and assessment of audiometric data. Results: A total of 4 patients were included (3 females and 1 male, mean age of 29.5 years [SD 19.8]). All patients (4/4) had a revision-free follow-up during a mean of 24.5 (SD, 6.19) months. Reinfections (n = 3) were observed in 2 patients (2/4) occurring 1 and 15, as well as 8 months after surgery. Reinfections could be successfully treated using topically and/or orally applied antibiotic therapy. No change in air-conducted pure-tone average was observed after treatment (mean change 1.3 dB; P = 0.99). Conclusion: Local application of antibiotic-loaded calcium sulfate pellets in combination with surgical debridement represents an effective treatment for local infection control in difficult-to-treat cases of temporal bone infections.