Background: The local recurrence rate of oral squamous cell carcinomas (OSCC) hardly decreases despite the best possible treatment. Partly, this is caused by the presence of (pre)malignant cells in the surrounding tissue, which can develop into a new malignancy in time. Histological recognition of these cells in resection margins appears to be difficult during routine practice. The aim of this study was to determine whether or not the presence of immune cells in OSCC resection margins may predict the development of a recurrence in these patients. Methods: Thirty-four patients with firstly diagnosed, radically resected primary OSCC with histopathological confirmed tumor-free margins (treated between 1993 and 2003) were included. Nine patients out of the 34 patient developed a locoregional recurrence within 5 years. Formalin-fixed paraffin-embedded tissue sections of 34 resection margins were subjected to immunohistochemistry for CD45, CD3, CD4, CD8, PD-L1 and PD-1 expression in immune cells, after which a quantitative analysis of the largerst distribution of CD45-, CD3-, CD4-, CD8-, PD-L1 and PD-1 positive lymphocytes on each resection margin has been photographed. The highly immunostained surface in relation to the total surface has been measured up to 100μm below the squamous epithelium. This analysis has been performed using QWin software (Leica). All data were analyzed using GraphPad Prism (version 7.05 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com). Results: Only CD3 and CD8 had a moderate correlation (Spearman = 0.68). A high expression of CD45 (≥7.7% ) and CD4 (≥5,4%) was strongly correlated with a worse disease-free survival (p = 0.0054 and p < 0.001, respectively), as was a low CD3 expression (≤5,9%) (p = 0.0211). PD-L1 and PD-1 expression analysis did not show a significant association with recurrence risk. Conclusions: A high amount of CD45-, and CD4- and a low amount of CD3-positive immune cells in OSCC resection margins may predict local recurrence.