In patients with solid malignancies, serum levels of specific acute phase proteins (haptoglobin, α 1-acid glycoprotein, and α 1-antitrypsin) have been correlated with parameters of both tumor extent and cellular immunity, while α 2HS-glycoprotein and prealbumin have been correlated with parameters of cellular immunity. To determine the relation of the glycoproteins to these parameters in head and neck squamous carcinoma, serum levels were measured in 90 untreated patients, 51 cured patients, 11 patients with recurrent carcinoma, and 20 patients during preoperative chemotherapy. The control patients were 139 chronic cigarette smokers. Haptoglobin levels were significantly increased in patients with stage I through IV tumors (AJC-1977), but levels were similar for each stage. Serum levels of α 1-antitrypsin and α 1-acid glycoprotein increased progressively with increasing tumor stage. Serum α 2HS-glycoprotein, prealbumin, and albumin levels were decreased in all patients, and α 1HS-glycoprotein levels decreased progressively with increasing tumor stage. When patients were classified into those with local tumors only and those with regional metastases, and further subclassified by extent of local or regional tumor, the acute phase proteins generally increased with increasing local or regional tumor extent and α 2HS-glycoprotein levels tended to decrease in the same groups. In cured patients, haptoglobin and α 1-acid glycoprotein levels were significantly lower and α 2HS-glycoprotein and prealbumin significantly higher than in untreated patients. Protein levels in patients with recurrent tumors were similar to levels in untreated patients. During acute immunosuppressive chemotherapy, levels of T-cells and α 2HS-glycoprotein decreased significantly and similarly, and after completion of chemotherapy, rebounded to pretreatment levels, while α 1-antitrypsin levels increased and haptoglobin and α 1-acid glycoprotein levels did not change. The data show that α 1-antitrypsin and α 1-acid glycoprotein correlate better with AJC tumor stage than cellular immune parameters previously studied and that α 2HS-glycoprotein levels may be as useful as T-cell levels for monitoring immune reactivity in patients with squamous cancer of the head and neck. These results suggest the potential of these biologic parameters as adjuncts in the derivation of improved staging systems and as indicators of tumor status and immune reactivity in patients with squamous carcinoma of the head and neck.