High-risk cutaneous squamous cell carcinoma (cSCC) is associated with poor clinical outcomes. Traditionally, preoperative clinical tumor size ≥2 cm, based on Brigham and Women's Hospital (BWH) staging criteria, is high risk. To compare outcomes of cSCC treated with Mohs micrographic surgery (MMS) with a preoperative size ≥2 cm (clinically ≥2 cm) versus cSCC with preoperative size <2 cm and postoperative defect size ≥2 cm (histologically ≥2 cm). Prospective data were collected from January 1, 2014, to December 31, 2020, on MMS cases for cSCC with a preoperative and/or postoperative size ≥2 cm. Clinical outcomes were followed until March 15, 2023. Data were analyzed using multivariate regression. Three hundred thirty cases of MMS for cSCC were included. Cutaneous squamous cell carcinoma clinically ≥2 cm occurred more frequently in elderly patients; cSCC histologically ≥2 cm were more commonly located in the H region, required wider surgical margins, and more MMS stages to achieve clearance. There were no significant differences in rates of recurrence and metastasis between the groups. These data suggest that postoperative (histologic) MMS defect size may allow for better risk stratification of high-risk cSCC and improved staging of cSCC.