Context .- Medical error is a significant problem in the United States, and pathologic diagnoses are a significant source of errors. Prior studies have shown that second-opinion pathology review results in clinically major diagnosis changes in approximately 0.6% to 5.8% of patients. The few studies specifically on head and neck pathology have suggested rates of changed diagnoses that are even higher. Objectives .- To evaluate the diagnostic discrepancy rates in patients referred to our institution, where all such cases are reviewed by a head and neck subspecialty service, and to identify specific areas with more susceptibility to errors. Design .- Five hundred consecutive, scanned head and neck pathology reports from patients referred to our institution were compared for discrepancies between the outside and in-house diagnoses. Major discrepancies were defined as those resulting in a significant change in patient clinical management and/or prognosis. Results .- Major discrepancies occurred in 20 cases (4% overall). Informative follow-up material was available on 11 of the 20 patients (55.0%), among whom, the second opinion was supported in 11 of 11 cases (100%). Dysplasia versus invasive squamous cell carcinoma was the most common (7 of 20; 35%) area of discrepancy, and by anatomic subsite, the sinonasal tract (4 of 21; 19.0%) had the highest rate of discrepant diagnoses. Of the major discrepant diagnoses, 12 (12 of 20; 60%) involved a change from benign to malignant, one a change from malignant to benign (1 of 20; 5%), and 6 involved tumor classification (6 of 20; 30%). Conclusions .- Head and neck pathology is a relatively high-risk area, prone to erroneous diagnoses in a small fraction of patients. This study supports the importance of second-opinion review by subspecialized pathologists for the best care of patients.