Background: To evaluate the therapeutic effects of combining epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with radiotherapy on the prognosis of patients with stage IV lung adenocarcinomas (LUAD) that harbor either exon 19 deletion (19-Del) or exon 21 L858R mutation (21-L858R). Methods: Clinical data in the real-world study were retrospectively collected and analyzed from 177 stage IV LUAD patients who received the combination of EGFR-TKIs and radiotherapy at Shandong Cancer Hospital between June 2012 and August 2017. And the primary endpoint of the study was overall survival (OS). Results: The results revealed that the stage IV LUAD patients harboring 19-Del showed similar clinical characteristics as those harboring 21-L858R (all P> 0.05). The median OS (mOS) of all patients was 32.0 (95%CI, 28.6-35.5) months. Multivariate analysis identified EFGR mutations and thoracic radiotherapy as the independent factors in predicting OS (P = 0.001, 0.013, respectively). Moreover, subgroup analysis showed that patients who received EGFR-TKIs plus bone metastasis radiotherapy or thoracic radiotherapy showed a longer OS in 19-Del group than those in 21-L858R group (mOS, 34.7 vs. 25.1 months, 51.0 vs. 29.6 months; P = 0.0056, 0.0013, respectively), while not observed for patients with brain metastasis radiotherapy (mOS, 34.7 vs. 25.1 months; P = 0.088). Conclusions: Although there were no significant differences in clinical characteristics of stage IV LUAD patients between 19-Del group and 21-L858R group, patients harboring 19-Del could still achieve longer OS than those harboring 21-L858R after receiving EGFR-TKIs in combination with radiotherapy.