Background: Diffusing capacity (Dlco), an independent predictor of morbidity after major lung resection, is not used routinely in preoperative evaluation because of a perceived lack of value in patients with normal spirometry. We evaluated the potential utility of measuring Dlco for assessment of operative risk in lung resection patients with normal spirometry. Methods: A retrospective review was conducted for patients undergoing lung resection from 1980 through 2006 to identify predictors of postoperative morbidity. Patients were divided into groups with or without chronic obstructive lung disease (COPD), defined as a ratio of forced expiratory volume in the first second to forced vital capacity of less than 0.7 or a ratio of 0.7 or greater, respectively. Analyses for each group identified covariates for three outcomes: operative mortality, pulmonary morbidity, and overall morbidity. Results: Of 1,046 patients in the database, 1,008 (545 men; mean age, 61.8 +/- 0.35 years) had data permitting determination of COPD status: 450 (45%) with COPD, 558 (55%) without COPD. Operations included lobectomy (752; 75%), bilobectomy (83; 8%), and pneumonectomy (173; 17%). Overall mortality, pulmonary morbidity, and overall morbidity incidences were 59 (5.8%), 140 (14.0%), and 311 (31.4%), respectively. Pulmonary morbidity and operative mortality were related to postoperative predicted Dlco, age, and performance status in patients with and without COPD. The postoperative predicted Dlco was the single strongest predictor of pulmonary morbidity and operative mortality in both patient groups. Overall complications were related to postoperative predicted Dlco only in the COPD group. Conclusions: Diffusing capacity is an important predictor of postoperative morbidity after lung resection even in patients with normal spirometry. Routine measurement of Dlco, regardless of spirometric findings, can help predict risk in candidates for major lung resection.