Indeterminate solitary pulmonary nodules (SPNs), measuring up to 3 cm in diameter, are incidental radiological findings. The ever-growing use of modern imaging has increased their detection. The majority of those nodules are benign; however, the possibility of diagnosing early-stage lung cancer still stands. Guidelines for the management of SPNs have never been validated in prospective comparative studies. Positron emission tomography (PET) is a useful tool to provide functional information on SPNs. However, overall sensitivity and specificity of PET in detecting malignant SPNs of at least 10 mm in diameter are about 90% and false-negative results are reported. The development of video-assisted thoracic surgery has provided minimally invasive diagnosis and treatment of SPNs. In our series, 105 patients underwent surgery based on combined increased 18F-labelled 2-fluoro-2-deoxy-d-glucose (FDG) uptake on PET computed tomography and radiological features (morphology and density) without prior histological confirmation. We detected 26 false negatives (24.8%) and only nine false positives (8.57%). Therefore, our minimally invasive surgical approach prevented 25% of patients with lung cancer from a delayed treatment versus only 9% undergoing "overtreatment". In our monocentric cohort, patients with SPNs with large diameter, irregular outline, no calcifications, central location, increased FDG uptake and/or subsolid aspect benefited from a primary surgical resection.