Large format histology offers several unique advantages over traditional tissue processing. Over 12 years of experience with this technique provide insight into its limitations and benefits. We conducted a prospective multiyear analysis of the potential advantages of large format histology. 656 cases were examined prospectively over an eight-year period. In 172 cases the sign-out pathologist documented an unexpected finding of potential clinical significance as present only on the large format sections and not present on the accompanying standard format slides. These include closer margins, a change in size or extent of disease, and previously undocumented invasive and/or in situ carcinoma. Based on over a decade of experience and eight years of data, our results demonstrate that a quarter of cases had an unexpected finding of potential clinical significance that may not have been fully realized without the use of the large format technique.