Objective This study aimed to analyze the relationship between the mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) and their impact on the prognosis and treatment of lung adenocarcinoma. Methods A total of 158 cases of lung adenocarcinoma reported between January 2007 and January 2014 were retrospectively analyzed. These tumors were resected using radical pneumonectomy and underwent pathology-based diagnosis at our institution (Inner Mongolia People\'s Hospital, Hohhot, China). The tissue sections were evaluated using the updated World Health Organization classification of lung adenocarcinomas (2015 version), with each histological component recorded in 5％ increments. The histological subtypes were classified, and any surviving cases were followed up. The reverse transcription-polymerase chain reaction (RT-PCR) and direct DNA sequencing were used to evaluate mutations in exons 18, 19, 20, and 21 in the EGFR gene, and the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) fusions were detected using sequencing. Results Our cohort included 25 patients with pre-invasive adenocarcinoma, 13 patients with lepidic, 66 patients with acinar, 13 patients with papillary, and 25 patients with solid infiltrative adenocarcinoma with the remaining cases presenting with a variety of pathological subtypes. The prognosis of each histological subtype was different with the 5-year disease-free survival and 5-year overall survival (OS) of pre-invasion adenocarcinoma at 100％; the 5-year OS of lepidic, acinar, and papillary adenocarcinoma patients was only 84.6％, 72.7％, and 76.9％, respectively. The 5-year OS of solid and mucinous adenocarcinomas were 32.0％ and 36.4％, respectively. EGFR mutation was detected in 69 cases with a mutation rate of 43.7％ and majority of these mutations were found in exons 19 (50.6％) and 21 (37.9％), with women and non-smokers shown to experience a higher mutation rate (P < 0.05). However, histological subtype analysis showed that EGFR mutations were primarily found in adenocarcinomas. Most of these mutations were found in lepidic (53.8％) or acinar adenocarcinomas (50.0％), whereas these mutations were rare in both solid (28.0％) and mucinous adenocarcinoma (27.2％). The fusion mutation rate in the EML4-ALK gene was 5.69％, and was most common in young, nonsmoking patients (P < 0.05). Conclusion The prognosis of patients in each lung adenocarcinoma subtype is different, and these outcomes are likely related to mutations in the EGFR and EML4-ALK genes. EGFR mutation rates are higher in lepidic and acinar adenocarcinomas, whereas EML4-ALK gene fusion mutations are more common in solid and mucinous adenocarcinoma. EGFR mutations are more common in female and non-smoking patients, whereas EML4-ALK fusions are more common in young, non-smoking patients.