High expression of S-phase kinase associated protein 2 (Skp2) is associated with numerous clinicopathological parameters, including histology, lymph node metastasis, smoking status, differentiation and Tumor-Node-Metastasis stage in non-small cell lung cancer (NSCLC). Skp2 protein is overexpressed in lung squamous cell carcinoma (LUSC), compared with lung adenocarcinoma (LUAD), whilst the clinicopathological and prognostic implications in LUAD or LUSC remain unclear. A larger study is required to assess the differences in Skp2 expression between these NSCLC types. In the present study, the clinicopathological features and immunohistochemical expression of the Skp2 protein were studied in 500 patients with NSCLC (351 with LUAD and 149 with LUSC). Survival analyses were performed using Kaplan-Meier method and Cox regression model. Skp2 associated genes were identified based on the data from The Cancer Genome Atlas database. Skp2 was overexpressed in patients with LUSC, compared with LUAD (P<0.001). In histology subgroup analysis, differences in Skp2 protein expression were observed in patients with LUAD, based on sex, differentiation, smoking history, stage, lymph node metastasis and tumor diameter (P<0.05), but not in patients with LUSC except for smoking status. High Skp2 protein expression in patients with LUAD was associated with reduced overall survival (OS; P<0.001), but not in patients with LUSC (P=0.686). The multivariate analysis demonstrated that Skp2 expression is an independent unfavorable prognostic factor for OS in patients with LUAD (RR=1.845, P<0.05). Bioinformatics analyses revealed that minichromosome maintenance complex component 2, cell division cycle 45, replication factor C subunit 4, which are differently expressed in LUAD and LUSC, are associated with Skp2 expression and participate in DNA replication and G/S transition. Skp2 protein expression differs in LUAD and LUSC. The clinicopathological and prognostic implications based on Skp2 expression in LUAD and LUSC should be considered different. LUSC with high Skp2 expression may have robust proliferation ability.