The present study aimed to analyze the differentially expressed genes related to the tripartite motif containing 58 (TRIM58)/cg26157385 methylation sites, and consequently to provide theoretical basis for elucidating the influence of TRIM58/cg26157385 methylation on lung cancer prognosis. Methylation‑sequencing information, mRNA expression profiling data and clinical data were downloaded from cBioPortal database to screen out candidate genes related to the methylation of TRIM58/cg26157385 in squamous cell lung carcinoma. The differentially expressed genes related to TRIM58 methylation were extracted form both training dataset and validation dataset. Cox regression analysis, risk scoring system construction, correlation analysis between the expression value of genes and clinical information were conducted to reveal TRIM58 methylation‑related factors. Additionally, GO function analysis and KEGG pathway enrichment analysis were performed. Based on their expression level and the corresponding survival information for 347 out of 370 samples with squamous cell lung carcinoma, 183 genes significantly associated with prognosis were gained, and the top 8 ones, including alpha‑2‑macroglobulin‑like 1 (A2ML1), cyclin‑E1 (CCNE1), COBL, establishment of sister chromatid cohesion N‑acetyltransferase 2 (ESCO2), G protein‑coupled receptor 115 (GPR115), matrix metalloproteinases 10 (MMP10), OVO homologue‑like 1 (OVOL1) and secretoglobin family 1A member 1 (SCGB1A1), were candidate signature genes significantly correlated with TRIM58 methylation. Furthermore, targeted therapy was significantly correlated with prognosis. Functional enrichment analysis demonstrated that the proliferation and differentiation of epidermal cells in lung squamous cell carcinoma patients were abnormal and the homeostasis was disturbed. Eight genes, including A2ML1, CCNE1, COBL, ESCO2, GPR115, MMP10, OVOL1 and SCGB1A1, were significantly related to TRIM58 methylation and treatment of lung squamous cell carcinoma, and may be used as potential prognostic biomarkers. The present study would help to elucidate the influence of TRIM58/cg26157385 methylation on lung cancer prognosis.