Background: The local recurrence rate in oral squamous cell cancer (OSCC) hardly decreases. This is partly due to the presence of (pre) malignant cells in the remaining tissue after resection, that may lead to the development of a new tumor in time. Detection of histologically (pre) malignant cells in the tumor resection margins should predict these patients at risk for recurrence, however this appears to be difficult in routine practice. Purpose of this study was to apply easy-to-use molecular tests for more accurate detection of (pre) malignant cells in histopathologically tumor-free margins, to improve diagnosis of patients at risk. Methods: 42 patients with firstly diagnosed, radically resected primary OSCC with histopathologically confirmed tumor-free resection margins (treated between 1994 and 2003) were included. Inclusion criteria comprised of follow-up >= 5 years, and radical surgery without postoperative treatment. Formalinf-ixed paraffine-embedded tissue sections of 42 tumors, 290 resection margins, and 11 recurrences were subjected to fluorescence in situ hybridization (FISH) to examine chromosome 1 and 7 copy number variations (CNV), and to p53 immunohistochemistry (IHC). Results: 11 out of the 42 patients developed a local recurrence within 5 years. FISH analysis showed that nine of eleven recurrences exhibited CI in at least one of the resection margins (p = 0.008). P53 overexpression and routine histopathologic classification were not correlated with recurrent disease. The presence of CI in the resection margins revealed a significantly worse progression-free survival (log-rank p = 0.012). Conclusions: CI in the resection margins of OSCC can reliably identify patients at risk for developing a local recurrence. (C) 2016 Elsevier Ltd. All rights reserved.