OBJECTIVE: To evaluate chromosomal instability at 9p21-22 with p16 protein expression in organ transplant recipients (OTRs) compared with immunocompetent patients with squamous cell carcinoma (SCC). DESIGN: In a select population of intraepithelial and subsequent invasive SCC from the same anatomic region of the same patient at different times, we assessed loss of heterozygosity at 3 microsatellites-IFNA, D9S162, and D9S925-in the course of carcinogenesis in OTRs and immunocompetent patients. SETTING: Department of Dermatology, University Hospital Zurich. Patients Immunocompetent patients and OTRs with SCC on sun-damaged skin. Main Outcome Measure Chromosomal allelic balance in SCC of OTRs and immunocompetent patients. RESULTS: Reduced allelic balance at IFNA, D9S162, and D9S925 in intraepithelial forms of SCC and similar allelic imbalance in invasive forms of SCC were found. Allelic balance at D9S162 was reduced for SCC in OTRs compared with SCC in immunocompetent patients. The study revealed broadly reduced allelic balance at 9p21-22 in all cutaneous SCCs, and OTRs presented a further reduced allelic balance for D9S162, suggesting a common trait for SCC in OTRs. Actinic keratosis and Bowen disease differed in allelic balance at D9S162, suggesting substantial differences in their carcinogenesis. Conclusion Reduced allelic balance around locus D9S162 is a genomic correlate for enhanced carcinogenesis in OTRs.