Second opinion in pathology is intended to expose clinically significant errors that have a direct impact on patient care. Before definitive treatment of referred patients, our institution requires a second opinion of outside surgical pathology slides. We sought to determine if this local standard of practice has a measurable impact on patient care via clinical and pathologic follow-up. 5629 second opinion surgical pathology cases seen at the University of Iowa Hospitals and Clinics were studied. Each case was classified as: no diagnostic disagreement, minor diagnostic disagreement, or major diagnostic disagreement by the second opinion pathologist at the time of referral. A major diagnostic disagreement was defined as a change in pathologic diagnosis with potential for significant change in treatment or prognosis. Major diagnostic disagreements were categorized by organ system and according to the clinical significance of the changed diagnosis based on clinical and pathologic follow-up. Second opinion surgical pathology resulted in 132 (2.3% of total cases) major diagnostic disagreements and 507 (9.0%) cases with minor disagreements. The organ systems involved in the majority of the major disagreements were the female reproductive tract (32), gastrointestinal tract (27), and skin (24). Of the 132 major diagnostic disagreements, 68 (1.2% of total cases reviewed) prompted changes in the clinical management as a result of the second opinion interpretation. These findings support the idea that mandatory second opinion is an important part of patient care in the referral setting.