Background: The purpose of this preliminary study was to evaluate the efficacy of positron emission tomography (PET) with [18F]fluoro-2-deoxyglucose (FDG) for differentiating benign from malignant solitary pulmonary nodules. Methods: Twenty-six patients (12 females, 14 males, age 27–79 years) with radiographically indeterminate solitary pulmonary nodules underwent FDG-PET and the findings were compared with the results of pathological examination of biopsy samples. FDG activity in the lesion was expressed as the ratio of lesion-to-background counts (L/B ratio) for semiquantitative analysis. Results: The mean L/B ratio of malignant lesions (8.81 3.71, n = 20) was not significantly higher than that of benign lesions (4.71 3.00, n = 6) (p = 1.00). Using a cut-off L/B ratio of 5.0 for malignancy, FDG-PET correctly detected 19 true positive and three true negative cases, but failed to detect three false positive (two abscesses and one cryptococcus) cases and one false negative (adenocarcinoma) case. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 95, 50, 86, 75 and 85%, respectively. Conclusions: FDG-PET is a sensitive modality for detecting malignancy, but is not specific enough. Benign lung lesion with active inflammation could demonstrate high FDG uptake, making it difficult to differentiate from malignancy. In the future, we will increase the case numbers to evaluate further the utility of FDG-PET for differentiating radiographically indeterminate solitary pulmonary nodules.