Second primary tumors and recurrences are an important problem in patients with head and neck squamous cell carcinoma. The purpose of this study was to determine the genetic changes in tumor samples to improve knowledge of tumor progression.,Copy number changes of 37 genes were analyzed by multiplex ligation-dependent probe amplification (MLPA) in 36 primary tumors and their corresponding 21 second primary tumors and 15 recurrences.,CCND1 and EMS1 amplifications and gain of BCL2L1 were the most common genetic alterations in the primary tumor, second primary tumor, and recurrence samples. Gains of ERBB2 and PTPN1 were associated with recurrences.,Specific genetic profiles for each group have been found. Similarities between primary tumor and second primary tumor and dissimilarity between primary tumor and recurrence suggest that clinicopathological criteria do not always accurately differentiate these entities. Genetic profiling may aid in the diagnosis and prognosis of these difficult cases.