To investigate the differences between lung adenocarcinoma with the pleural invasion that has EGFR (epidermal growth factor receptor) 19-del or 21L858R mutations in terms of clinical characteristics and outcomes. EGFR mutation-positive patients with pleural metastasis of lung adenocarcinoma diagnosed in the Department of Respiratory Medicine of Yuhuangding Hospital of Yantai City, Shandong Province, from January 2014 to January 2022 were selected. The clinical data of the patients were collected to retrospectively analyze whether the clinical characteristics and prognosis of patients with 19-del or 21L858R mutation subtype were different and analyze the impact of clinical characteristics on the prognosis of patients. The difference in clinical characteristics between the 2 groups was analyzed by SPSS,P< .05. There was statistical significance. Univariate and multivariate regression analysis was performed with R soft. To establish a 2-year overall survival predictive model for patients with EGFR gene 19-del and 21L858R mutations in patients with pleural invasion of lung adenomas and to provide predictive model maps. Receiver operating characteristic curve, calibration curve, and decision curve analysis were used to evaluate the value of the prediction model in this study. Of the 74 patients included, the 19-del mutation group had a higher incidence of pleural thickening (P= .023) and a lower Ki-67 level (P= .035). There was no difference in 2-year overall survival and progression-free survival between the 2 mutations. There were differences in pleural thickening and Ki-67 index between the 2 groups, but no differences in disease outcome between the 2 groups. The nomogram model established based on gender, treatment regimen, CEA, lymph node metastasis, and pleural changes is accurate and feasible.