Processing of adipose-rich Mohs micrographic surgery (MMS) specimens poses challenges that may preclude complete margin evaluation. In this setting, the value of additional freezing methods using various cooling agents has not been previously investigated. The aim of this study is to compare the frozen section quality of high-adipose Mohs specimens processed without additional cooling treatments versus those pretreated with 1,1,1,2-tetrafluoroethane (TFE) or liquid nitrogen (LN2). A set of 3 sections were each taken from 24 adipose-rich Mohs micrographic surgery specimens. A section from each set was subjected to either no additional cooling treatment (control), two 10-second pulse sprays of 1,1,1,2-tetrafluoroethane, or three 2-second pulse sprays of LN2. After staining, 2 blinded raters evaluated slide quality based on the presence or absence of the following features: margin completeness, nuclear clearing, epidermal or adipose folding, holes, or venetian blind-like artifacts. Pretreatment of the sample with LN2 produced a significantly (P < 0.001) greater number of high-quality slides (19/24) compared to pretreatment with 1,1,1,2-tetrafluoroethane (1/24) and no additional treatment (0/24). The adjunctive use of LN2 spray before tissue embedding circumvents the challenges of processing “thick” (high-adipose) specimens and facilitates the production of high-quality frozen section slides during Mohs micrographic surgery.