Abstract Objective: To analyse the role of surgery along with antimicrobials to improve clinical outcomes in treating refractory cases of skull base osteomyelitis (SBO). Study design and setting: A prospective comparative study in a tertiary care centre with 70 SBO patients meeting eligibility criteria. Participants: The study population comprised 35 patients refractory to systemic antimicrobials of at least four weeks duration who later underwent surgery in addition to medication (surgical group). They were compared with a medical group that responded to medications alone. Main outcome measures: The outcome variables studied were the resolution of clinical features (pain, discharge, radiology, and inflammatory markers), culture yield, and total duration of treatment. Results: According to our study, relief of pain was faster in the surgical group(1.66 against 4.57 months) with statistical significance (p< 0. 001). Relief of symptoms (p< 0.001), radiological improvement (p= 0.001), and normalizing of inflammatory markers (p<0.001) were better in the surgical group than in the medical group. The duration of treatment was an average of 9. 2 months in the surgical group compared to 11.3 months in the medical group (p= 0.019). Microbial culture from deep tissue sampling was positive in 24 surgical patients (68.57%). Conclusion: The treatment response to surgery and antimicrobials in treating refractory cases of SBO was better than the group who responded to antimicrobials alone. Surgery provided higher microbial yield resulting in culture-specific antimicrobials. The surgical group observed faster relief of symptoms, reduced hospital stay, and total treatment duration.