This study was undertaken to investigate the potential role of xenografts established from human head and neck squamous cell carcinoma (HNSCC) in the selection of new anticancer agents for phase M clinical trials. Eight HNSCC tumor lines were established in NMRI nude mice. The tumor‐bearing animals were then treated with drugs at the maximum tolerated dose level. Treatment with drugs known for their activity in 15%–30% of HNSCC patients [cisplatin (CDDP), bleomycin (BLEO), 5‐fluorouracil (5‐Fu), cyclophosphamide (CY), and doxorubicin (DOX)] caused strong responses in up to 38% and moderate responses in 50%–67% of the HNSCC tumor lines. Methotrexate (MTX), known to cause remissions in about 40% of HNSCC patients, was only minimally active in this model system. A clinically ineffective drug, amsacrine (m‐AMSA), was included as a negative control and showed no or minimal activity in all four HNSCC lines tested. A number of experimental drugs that have promising preclinical activity were also tested. Brequinar sodium (Dup 785) and 10‐ethyl, 10‐deaza‐aminopterin (10‐EdAM) showed activity in three of five, and two of the four tested tumor lines respectively. N, N‐dimethylformamide (DMF) and 5‐aza‐2′‐deoxycytidine (5‐aza‐dCyd), agents with the capacity to induce differentiation in in vitro systems, showed moderate activity in 43% and 40%, and strong activity in 14% and 40% of the lines, respectively. Our results indicate that the nude mouse xenograft model may play a role in the screening of new drugs, and in particular, it could be of help in the selection of drugs to be tested in phase II HNSCC clinical trials.