We report a retrospective review of 223 patients who presented to the Department of Head and Neck Surgery from 1970 through 1987 with a diagnosis of metastatic adenocarcinoma of unknown primary origin. Multivariate analysis was performed using the following parameters: age, sex, initial side and site of nodal involvement, involvement of other body sites, degree of differentiation, treatment modality, outcome, and survival. Follow-up was obtained in all patients, with a minimum of 2 years for survivors. Average age was 55 years, with an approximately equal male:female ratio. The most common site of presentation was the supraclavicular fossa (76%). The initial side of presentation was the left neck in 53% of patients, right neck in 33%, and bilateral in 14%. Metastatic disease to other body sites was present in 86% of patients, with the most common sites being mediastinum (35%), lung (21%), and bones (19%). Increased survival was associated with unilateral neck involvement (p = 0.001) and disease limited to nodes above the cricoid cartilage (p = 0.007). Mean survival was 17 months, with a median of 8 months. Death was due to the index cancer in all but four patients; three of these four patients died of treatment-related causes. Survival was 20% at 2 years and 9% at 5 years. Length of survival was not affected by age, sex, initial side of neck disease, location of other metastatic sites, histologic appearance, or treatment modality. Our current algorithm for the work-up and treatment of this lethal disease is explained.