We evaluated the diagnostic yield of open-lung biopsies (OLBs) in a large tertiary cancer center to determine the role of infectious diseases as causes of undiagnosed pulmonary lesions. All consecutive adult patients with either single or multiple pulmonary nodules or masses who underwent a diagnostic OLB over a period of 10 years (1998–2007) were retrospectively identified. Their risk factors for malignancy and clinical and radiological characteristics were reviewed, and their postoperative complications were assessed. We evaluated 155 patients with a median age of 57 years (range, 19–83 years). We identified infectious etiologies in 29 patients (19 %). The most common diagnosis in this group was histoplasmosis (12 [41 %]), followed by nontuberculous mycobacterial infection (7 [24 %]) and aspergillosis (4 [14 %]). The majority of the 126 remaining patients had nonmalignant diagnoses, the most prevalent being nonspecific granuloma (26 %), whereas only 17 % had malignant diagnoses. We observed no significant differences among the patients with infectious, malignant, or both noninfectious and nonmalignant final diagnoses regarding their demographic, laboratory, and clinical characteristics. Six percent of the patients had at least one post-OLB complication, and the post-OLB mortality rate was 1 %. OLB is a safe diagnostic procedure which frequently identifies a wide variety of infectious and inflammatory diseases.