BACKGROUND CONTEXT: Collet-Sicard syndrome (CSS) is a rare condition that includes palsies of cranial nerves IX, X, XI, and XII. There are multiple reported causes in the literature, although infection is particularly unusual. PURPOSE: To report an unusual case of CSS as a result of infection causing head-to-neck dissociation with involvement of the upper cervical spine. STUDY DESIGN: Case report. METHODS: A 56-year-old male with medical comorbidities developed a cranial-based infection secondary to initial incomplete treatment of otitis media. The mass effect of the infection resulted in multiple cranial nerve palsies and extremity symptoms initially confused with a cerebrovascular accident. Clinical course of the patient and a review of CSS are presented. RESULTS: With progression of the disease, further evaluation revealed a disseminated upper cervical and skull-based infection causing destructive head-to-neck infectious instability. This was treated with posterior occipitocervical debridement, fixation, and fusion and appropriate long-term antibiotics. Over the course of several months, the infection resolved and there was a significant improvement in his dysphagia, dysarthria, and hearing. CONCLUSIONS: Delay in diagnosis of CSS is common, and this syndrome should be considered in patients who present with a constellation of lower cranial nerve palsies. Early recognition and treatment should result in successful recovery, but even in cases of delayed detection, suitable intervention can result in substantial clinical improvement.