Context .- Oropharyngeal squamous cell carcinoma is associated both with tobacco use and with human papillomavirus (HPV) infection. It is argued that carcinogen-driven tumorigenesis is a distinct disease from its virally driven counterpart. We hypothesized that tumorigenesis is the result of a loss of genotypic robustness resulting in an increase in phenotypic variation in tumors compared with adjacent histologically normal tissues, and that carcinogen-driven tumorigenesis results in greater variation than its virally driven counterpart. Objectives .- To examine the loss of robustness in carcinogen-driven and virally driven oropharyngeal squamous cell carcinoma samples, and to identify potential pathways involved. Design .- We used coefficients of variation for messenger RNA and microRNA expression to measure the loss of robustness in oropharyngeal squamous cell carcinoma samples. Tumors were compared with matched normal tissues, and were further categorized by HPV and patient smoking status. Weighted gene coexpression networks were constructed for genes with highly variable expression among the HPV(-) tumors from smokers. Results .- We observed more genes with variable messenger RNA expression in tumors compared with normal tissues, regardless of HPV and smoking status, and more microRNAs with variable expression in HPV(-) and HPV(+) tumors from smoking patients than from nonsmokers. For both the messenger RNA and microRNA data, we observed more variance among HPV(-) tumors from smokers compared with HPV(+) tumors from nonsmokers. The gene coexpression network construction highlighted pathways that have lost robustness in carcinogen-induced tumors but appear stable in virally induced tumors. Conclusions .- Using coefficients of variation and coexpression networks, we identified multiple altered pathways that may play a role in carcinogen-driven tumorigenesis.