The predictive power of age at diagnosis and smoking history for ALK rearrangements and EGFR mutations in non-small-cell lung cancer (NSCLC) remains not fully understood. In this cross-sectional study, 1160 NSCLC patients were prospectively enrolled and genotyped for EML4-ALK rearrangements and EGFR mutations. Multivariate logistic regression analysis was performed to explore the association between clinicopathological features and these two genetic aberrations. Receiver operating characteristic (ROC) curves methodology was applied to evaluate the predictive value. We showed that younger age at diagnosis was the only independent variable associated with EML4-ALK rearrangements (odds ratio (OR) per 5 years' increment, 0.68; p < 0.001), while lower tobacco exposure (OR per 5 pack-years' increment, 0.88; p < 0.001), adenocarcinoma (OR, 6.61; p < 0.001), and moderate to high differentiation (OR, 2.05; p < 0.001) were independently associated with EGFR mutations. Age at diagnosis was a very strong predictor of ALK rearrangements but poorly predicted EGFR mutations, while smoking pack-years may predict the presence of EGFR mutations and ALK rearrangements but with rather limited power. These findings should assist clinicians in assessing the likelihood of EML4-ALK rearrangements and EGFR mutations and understanding their biological implications in NSCLC.