Background: The human lysine oxidase-like 3 (LOXL3) is important in maintaining genome stability and promoting mitosis completion. Through a variety of mechanisms, LOXL3 regulates signal transduction pathways and participates in the carcinogenesis and development of multiple tumors. The purpose of the present study was to determine the association of LOXL3 with tumor progression and prognosis in pleural mesothelioma (PMe) patients. Methods: LOXL3 mRNA-SeqV2 and clinical data for PMe cases were obtained from TCGA with R3.6.3 to analyze the associations of LOXL3 mRNA amounts with clinicopathological parameters. The clinical data of the Chuxiong population were collected to assess the associations of LOXL3 protein amounts with clinicopathological parameters. LOXL3 protein and mRNA amounts were assessed by immunohistochemistry, Western blotting and qRT-PCR. Next, the prognostic value of LOXL3 in PMe was examined by a Cox regression model in multivariable analysis. Next, the relationships between the expression level of LOXL3 and clinicopathological characteristics and the prognostic value of LOXL3 were analyzed. Finally, the associations of LOXL3 expression with other LOXL family members were analyzed by GEPIA. GSEA identified 16 gene sets significantly enriched in PMe. Results:LOXL3 is upregulated at the mRNA and protein levels in human PMe compared with noncancerous pleural tissues. In addition, the mRNA and protein expression level of LOXL3 was significantly correlated with cancer type. The protein expression level of LOXL3 was significantly correlated with Wilms Tumor Protein(WT-1) level( P<0.05). Further analysis showed that cancer type was a prognostic factor in PMe. Further analysis showed that high expression level of LOXL3 was unfavorable in terms of the prognosis of patients with PMe. LOXL3 gene expression had a positive correlation with LOXL4 gene expression (R=0.26, P<0.05). High-LOXL3 expressing tissue samples were enriched in oxidative phosphorylation, adipogenesis, interferon alpha response and other genes. Low-LOXL3 expressing tissue samples were enriched in apoptosis, IL2-STAT5 signaling, mTORC1 signaling and other related genes. Conclusion: LOXL3 is associated with the occurrence and development of PMe. Our findings reveal that the elevated expression of LOXL3 may potentially predict poor overall survival (OS) in patients with PMe. More importantly, the expression level of the LOXL3 gene was significantly positively correlated with the expression of WT-1 genes and ancer type of PMe. As a new oncogene, LOXL3 deserves further investigation to validate its role and mechanism in PMe.