Lung cancer is the leading cause of mortalities among all types of cancer. Therefore, the screening of biomarkers that are related with the progression of lung cancer is crucial for early diagnosis and efficient therapy of lung cancer. In the present study, bioinformatic analysis identified replication factor C 5 (RFC5) as a potential novel oncogene in lung cancer. RFC5 functions as a clamp loader and is involved in DNA replication and repair. Analysis of public databases and reverse transcription-quantitative polymerase chain reaction indicated that RFC5 was significantly increased in tumor tissues compared with adjacent normal tissues. A high RFC5 expression was observed to be associated with more aggressive malignant clinicopathological features, including higher T stage, more advanced regional lymph node metastasis and a higher probability of relapse. Notably, there were notable differences in overall survival (OS), first progression and post-progression survival between the high RFC5 expression group and low RFC5 expression group. Univariate and multivariate Cox regression analyses indicated that RFC5 was an independent risk factor that was associated with poorer OS and disease-free survival. According to GSEA, several gene sets that are associated with cell cycle and DNA damage were enriched in the RFC5 overexpression group, which indicated that RFC5 might promote the proliferation of lung cancer cells. Our finding indicated that RFC5 might be a novel prognostic biomarker of lung cancer, and it might be serve as a potential diagnosis and therapy target for lung cancer in the future.