The authors have investigated whether genetic abnormalities in two genes, loss of heterozygosity (LOH) of p53 and amplification of the cyclin D1 gene, correlate with clinical outcome in 56 matched pairs of blood and tumor from patients with squamous cell carcinoma of the head and neck (SCCHN). Frequency of p53 LOH was 47.4%, of cyclin D1 amplification 33.9%, and of both abnormalities together 23.7%. p53 LOH was associated with T4 (P = 0.003) and stage IV (P = 0.015) tumors. Cyclin D1 amplification was associated with recurrences and/or metachronous tumors (P = 0.007). The total number of p53 and cyclin D1 abnormalities (scored as zero, one, and two) show a pattern that seems to be additive; the increase in the number of these abnormalities is associated with a proportional increase in the frequency of T4, stage IV, presence of recurrences and/or metachronous tumors, and possibly a proportional decrease in the disease-free interval in the sample. The association of the markers with recurrences and/or metachronous tumors persists if the tumor stage effect is mathematically removed. The combined analysis of the p53 and cyclin D1 abnormalities seems to be more informative than either of them individually and may have predictive value in SCCHN.