PURPOSE: To explore the potential parameters from F-FDG PET/CT that might be associated with the epidermal growth factor receptor (EGFR) gene mutation status in lung adenocarcinoma (ADC) patients. METHODS: Data of the test cohort of 191 patients and the validation cohort of 55 patients with newly diagnosed ADC were retrospectively reviewed. All patients underwent F-FDG PET/CT scans and EGFR mutation tests prior to treatment. The metabolic parameters obtained from F-FDG PET/CT combining with clinical characteristics were analyzed by using univariate and multivariate logistic regression analyses. Then two cohorts were enrolled to validate the predictive model by area under the receiver-operating characteristic curve (AUC), respectively. RESULTS: EGFR mutation-positive was seen of 33.0% (63/191) and 32.7% (18/55) in two cohorts, respectively. In univariate analysis, female, nonsmokers, metabolic parameters of primary tumor [mean standardized uptake value, metabolic tumor volume (pMTV), and total lesion glycolysis], non-necrosis of primary tumor, and serum tumor markers [carbohydrate antigen 19-9, squamous cell carcinoma antigen, and precursor of gastrin releasing peptide (proGRP)] were significantly relevant with EGFR mutation. In multivariate analysis with adjustment of age and TNM stage, pMTV (<8.13 cm), proGRP (≥38.44 pg/ml) and women were independent significant predictors for EGFR mutation. The AUC for the predictive value of these factors was 0.739 [95% confidence interval (CI) 0.665–0.813] in the cohort of 191 patients and 0.716 (95% CI 0.567–0.865) in the cohort of 55 patients, respectively. CONCLUSION: Low pMTV (<8.13 cm) was an independent predictor and could be integrated with women and high proGRP (≥38.44 pg/ml) to enhance the discriminability on the EGFR mutation status in ADC patients.