<h3>Objectives</h3> Oral squamous cell carcinoma is the most common multistep malignant tumor affecting the oral cavity. One of the most aggressive variants of this neoplasm is the basaloid squamous carcinoma. The cancer-associated fibroblasts in the tumor microenvironment are now the focus of intense research and are believed to correlate with poor prognosis. They are characterized by α-smooth muscle actin (α-SMA) expression, which is a myofibroblast marker. The aims of the present study were as follows: (1) to evaluate the role of α-SMA in the progression of both neoplasms, (2) to study the prevalence of this marker with different grades of this neoplasia, and (3) to determine the immunoreactive localization of α-SMA in the lymph nodes of patients with these tumors. <h3>Methods</h3> Twenty-one cases of squamous cell carcinoma and 7 cases of basaloid squamous carcinoma were included in this study, among which were 5 cases with cervical lymph node metastasis. These were distributed as 9 well-differentiated, 7 moderately, and 5 poorly differentiated cases. Immunohistochemical analysis using labeled streptavidin, biotin, and monoclonal antibody for α-SMA. <h3>Results</h3> Intense immunoexpression of α-SMA was observed in the anaplastic neoplasms that also was correlated with lymph node involvement. In contrast, well-differentiated cancer revealed only a mild reaction. <h3>Conclusions</h3> According to these findings, one could conclude that α-SMA can be used as a prognostic marker and potential target for cancer therapy.