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Simple Summary: Growth factor expression is a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). Targeted therapy has a limited effect on the treatment of advanced stages due to evolving resistance mechanisms. The aim of this study was to assess the distribution of growth factor receptors in oropharyngeal squamous cell cancer (OPSCC) and evaluate their role in the context of the human papillomavirus status, prognosis and possible relevance for targeted therapy. Tissue microarrays of 78 primary OPSCC, 35 related lymph node metastasis, 6 distant metastasis and 9 recurrent tumors were manufactured to evaluate the expression of human epidermal growth factor receptor (EGFR/erbB/Her)1–4 and c-Met by immunohistochemistry. EGFR and c-Met are relevant negative prognostic factors especially in noxae-induced OPSCC. Thus, dual targeting of EGFR and c-Met could be a promising prospective target in OPSCC treatment. Frequent coexpression of assessed receptors represents a possible intrinsic resistance mechanism in targeted therapy. This study aimed to assess the distribution of growth factor receptors in oropharyngeal squamous cell cancer (OPSCC) and evaluate their role in the context of human papillomavirus (HPV) status, prognosis and potential relevance for targeted therapy. The protein expression of human epidermal growth factor receptor (Her)1–4 and c-Met were retrospectively assessed using semiquantitative immunohistochemistry on tissue microarrays and analyzed for correlations as well as differences in the clinicopathological criteria. Her1–4 and c-met were overexpressed compared to normal mucosa in 46%, 4%, 17%, 27% and 23%, respectively. Interestingly, most receptors were coexpressed. Her1 and c-Met were inversely correlated with p16 (p = 0.04; p = 0.02). Her2 and c-Met were associated with high tobacco consumption (p = 0.016; p = 0.04). High EGFR, Her3, Her4 and c-Met expression were associated with worse overall and disease-free survival (p ≤ 0.05). Furthermore, EGFR and c-Met expression showed raised hazard ratios of 2.53 (p = 0.02; 95% CI 1.24–5.18) and 2.45 (p = 0.02; 95% CI 1.13–5.35), respectively. Her4 was expressed less in distant metastases than in corresponding primary tumors and was correlated to a higher T category. EGFR and c-Met are relevant negative prognostic factors in OPSCC, independent of known clinicopathological parameters. We suggest dual targeting of EGFR and c-Met as a promising strategy for OPSCC treatment. [ABSTRACT FROM AUTHOR]