The aim of the study is to observe retrospectively the correlation between Oral Squamous Cell Carcinoma (OSCC) and risk factors; including tobacco, alcohol and Family History of Cancer (FHC). A total of 478 patients were included retrospectively from the database of the Department of Oral Sciences and Maxillofacial Surgery, Sapienza University of Rome. A Test Group (TG) consisted of 239 patients with a confirmed diagnosis of OSCC. A Control Group (CG) consisted of 239 patients without history and/or diagnosis of oral cancer. The logistic regression models were used to calculate the adjusted Odd Ratios (ORs) associated with alcohol, tobacco and FHC; including the General Family History of Cancer (GFHC) and Family History of Head and Neck Cancer (FHHNC) and their 95% Confidence Intervals (CI). The high rate of tobacco consumption was associated with an OR of 1.035 (95% CI 1.001–1.070) and a statistical significance (p = 0.041). Drinker patients showed a significant risk of developing OSCC (p = 0.05) and the OR was 1.035 (95% CI 1.010–1.061). The GFHC was associated with a marginal risk of OSCC with an OR of 1.095 (95% CI 0.953–1.259), without significance (p = 0.199). The FHHNC showed a notable risk increase with an OR of 1.871 (95% CI 0.902–3.882), without significance (p = 0.092). Alcohol and tobacco may be associated with an increase in the risk of OSCC.