We managed five patients with large skull base defects complicated by complex infections with microvascular free tissue transfer. The first patient developed an infection, cerebrospinal fluid (CSF) leak, and meningitis after undergoing a translabyrinthine resection of an acoustic neuroma. The second patient had a history of a gunshot wound to the temporal bone, with a large defect and an infected cholesteatoma that caused several episodes of meningitis. The third through the fifth patients had persistent CSF leakage and infection refractory to conventional therapy. In all cases prior attempts of closure with fat grafts or regional flaps had failed. Rectus abdominis myofascial free flap, radial forearm free flap or a gracilis muscle free flap was used after debridement of the infected cavities. The CSF leaks, local infections, and meningitis were controlled within a week. In our experience, microvascular free tissue provides the necessary bulk of viable, well-vascularized tissue, which not only assures a mechanical seal but also helps clear the local infection.