We evaluated the efficiency of FDG PET/CT for the differentiation of malignant from benign mediastinal masses and neurogenic tumors of chest-wall. Methods: The 88 patients with chest wall-mediastinal masses who underwent examination before operation were retrospectively reviewed. Size, CT density (HU mean) and SUVmax of mediastinal and chest wall lesions were determined. Statistical differences of these parameters were compared between groups by Mann-Whitney U test. Receiver-operating characteristic curve (ROC) analysis with respect to SUVmax was performed to determine the best cutoff value for differentiating benign from malignant masses. Results: The overall sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT in detection of malignancy were 90%, 55.17%, 67%, 50.94% and 91.43%, respectively. The SUVmax, HU mean and size were higher in malignant cases (P < 0.05). To distinguish benign and malignant lesions, the cut off value of SUVmax was 4.67. The lesion SUVmax was significantly associated with the lesion size and lesion HU mean values (P < 0.05). The value of SUVmax and HU mean were higher in solid benign lesions than those of cystic benign lesions (P < 0.05). The lesion size was higher in cystic lesions (P = 0.000). The mean SUVmax was significantly higher in invasive thymomas than those of non-invasive forms (P = 0.029). Conclusion: FDG PET/CT may be complementary to conventional imaging methods for the evaluation of mediastinal and chest wall masses. PET/CT may reduce unnecessary invasive investigations for diagnosis in patients with nonavid or low avid FDG lesions. However confirmatory tissue sampling is required to confirm PET positive findings for the definite diagnosis.