Inclusion Criteria:  Previously untreated and biopsy confirmed oral squamous cell carcinoma (OSCC) Clinical (TNM) stage I or II Age >= 18 years Eastern Cooperative Oncology Group (ECOG) =< 2  Exclusion Criteria:  Patients associated with prior therapy requiring treatment with systemic immunosuppressive treatments with the exception of vitiligo, childhood asthma that has resolved, residual endocrinopathies requiring replacement therapy, or psoriasis that does not require systemic treatment Treatment with any other investigational agents Requirement for immunosuppressive intraoral topical or systemic corticosteroids prior to the study Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements HIV positive patients on combination antiretroviral therapy Have evidence of any other significant oral mucosal condition, clinical disorder, physical examination finding, or laboratory finding that, as judged by the investigator, makes it undesirable for the patient to participate in the study Pregnant women are excluded from this study because imiquimod may have adverse effect on the fetus (FDA pregnancy risk category C). Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with imiquimod, breastfeeding should be discontinued if the mother is receiving study treatment Male patients unwilling or unable to comply with pregnancy prevention measures Subjects not receiving initial surgical treatment at Columbia University Irving Medical Center (CUIMC).