The high tumor response rates associated with intensive chemotherapy in previously untreated patients with advanced head and neck squamous cell carcinoma (HNSCC) led to the initiation of a multi-institutional National Cancer Institute trial. This trial used preoperative chemotherapy in patients with resectable Stage III and IV squamous cell carcinoma of the oral cavity or larynx/hypopharynx. Response rates, toxicity, and a variety of patient and tumor characteristics were analyzed to determine which factors might be useful in predicting tumor response to preoperative chemotherapy. Two hundred eighty-two patients received one course of preoperative cisplatin and bleomycin chemotherapy and were evaluable. There were 22 complete responses (CR) and 114 partial responses (PR) at the primary site (48% response rate). Of 197 patients with clinically positive regional adenopathy, 29 CRs and 73 PRs were observed (52%). Toxicity associated with the chemotherapy regimen was minimal. Primary tumor and regional node responses to chemotherapy were strongly correlated. No significant differences were found in primary or nodal response rates with respect to differing tumor site, stage, histologic differentiation, patient performance status, nutritional status, leukocyte count, hemoglobin level, age, sex, or alcohol use. Primary tumor response, however, was significantly related to T classification (P = 0.048). Nodal response was strongly associated with N classification and nodal size (P = 0.02 and P = 0.075, respectively). These findings suggest that, of the patient and tumor characteristics analyzed, none were more useful in predicting tumor response than clinical tumor staging parameters.