The cases of 80 patients who underwent Caldwell-Luc surgery for the treatment of chronic rhinosinusitis between 2002 and 2007 at Vanderbilt University Medical Center's Department of Otolaryngology were reviewed. Data on demographics, comorbidities, details of surgery, surgical pathology, and histology were collected. These data were compared with those of 40 patients who underwent standard functional endoscopic sinus surgery in 2007. Statistically significant differences were found in terms of mean patient age, sex, mean number of sinuses surgically addressed, number of prior surgeries, and tissue eosinophil counts. Microscopic examination revealed the presence of “necrotic bone” in 2 Caldwell-Luc specimens, and “necrotic debris” in 2 other Caldwell-Luc specimens. No similar finding was seen in the control group. Caldwell-Luc is a surgery of last resort for patients who fail aggressive interventions for maxillary sinus disease. The mucosal lining of this small group of patients appears to be different from that of patients who respond favorably to functional endoscopic sinus surgery.