Recent studies have indicated that numerical chromosomal abnormalities including changes in p53 and cyclin D1 may be involved in Hurthle cell tumorigenesis. We analyzed a series of Hurthle cell neoplasms of the thyroid to evaluate the diagnostic and prognostic utility of numerical anomalies by DNA fluorescent probes for cyclin D1 and p53 gene loci and chromosomes 5, 7, 11, 12, 17, and 22. Interphase fluorescence in situ hybridization (FISH) analysis was performed on paraffin-embedded tissue sections from 10 Hurthle cell adenomas, 19 Hurthle cell carcinomas, and 7 normal thyroid tissues used as controls. Directly labeled fluorescent DNA probes for the centromere region of chromosomes 7, 11, 12, and 17 and locus-specific probes for chromosomes 5 and 22, cyclin D1, and p53 were utilized for dual-probe hybridizations. Sixty percent (6 of 10) Hurthle cell adenomas and 63% (12 of 19) Hurthle cell carcinomas showed chromosome gains. Twenty percent (2 of 10) Hurthle cell adenomas and 26% (5 of 19) Hurthle cell carcinomas showed chromosome losses. Normal thyroid tissues used as controls showed no chromosomal abnormalities. Among Hurthle cell tumors with chromosomal abnormalities, adenomas averaged 2.7 gains and 0.3 losses per case, and carcinomas averaged 3.3 gains and 0.6 losses per case. The two adenomas with chromosome losses each showed loss of one chromosome, whereas the five carcinomas with losses averaged 1.8 losses per case. Chromosome 22 was the most common loss identified, occurring in three of the 11 patients who died of disease. These results indicate that chromosomal imbalances as gains are common in both benign and malignant Hurthle cell neoplasms, but Hurthle cell carcinomas tend to have more chromosome losses than adenomas. Among Hurthle cell carcinomas in this study, chromosome losses were identified only from patients who died of disease. The loss of chromosome 22 may have prognostic value in Hurthle cell carcinoma of the thyroid.