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Lung cancer screening with low-dose computed tomography has demonstrated at least a 20% decrease in lung cancer-specific mortality, but it has the potential harm of unnecessary invasive procedures performed because of false-positive results. This study reports the outcomes of a structured multidisciplinary lung cancer screening program in an area of endemic histoplasmosis.A retrospective review of patients undergoing lung cancer screening from December 2012 to March 2019 was conducted. Findings suggestive of lung cancer were presented to a multidisciplinary thoracic tumor board. Patients were assigned to interval imaging follow-up, additional diagnostic imaging, or referral for an invasive procedure. Invasive procedures were then compared between benign and malignant diseases.A total of 4087 scans were performed on 2129 patients; 372 (9.1%) were suspicious and were presented to a multidisciplinary thoracic tumor board. Ultimately, 108 procedures were performed: 55 bronchoscopies, 7 percutaneous biopsies, and 46 operations. A total of 25 patients (1.2%) underwent bronchoscopy resulting in benign pathologic findings, significantly associated with an indication of an endobronchial lesion (P = .01). All percutaneous biopsy specimens revealed malignancy. Five patients (0.2%) who underwent resection had benign disease. Lung cancer was diagnosed in 67 patients (3.1% of the entire cohort), 46 of whom had stage I or II disease.Lung cancer screening in a structured, multidisciplinary program successfully identifies patients with early-stage lung cancer with limited unnecessary surgical interventions. Patients with isolated endobronchial lesions should undergo short interval imaging follow-up to avoid bronchoscopy for benign disease. Future studies to minimize unnecessary procedures could incorporate biomarkers and advanced imaging analysis into risk assessment models.