We looked for the involvement tumor suppressor gene (TSG) in lung cancer in 17q25 region by loss of heterozygosity analysis and 5'/3' RACE and identified a candidate gene named human RAB37 (hRAB37), which encodes a small GTPase. The Ras-GTPase superfamily functions as important regulators including membrane trafficking and cytoskeletal organization. Therefore, we further examined the mRNA expression and promoter/exon1 hypermethylation of hRAB37 gene in paired normal and tumor lung tissue from 71 non-small cell lung cancer (NSCLC) patients. Low hRAB37 mRNA expression occurred in 47.9% (34/71) of patient and promoter/exon1 hypermethylation of hRAB37 was found in 57.7% (41/71) of patients. Low mRNA expression of hRAB37 was significantly associated with their promoter/exon1 hypermethylation. Importantly, a reduction in hRAB37 mRNA expression and promoter/exon1 hypermethylation was found to be significantly associated with lung metastatic patients as compared to non-metastatic patients. 5-Aza-2-deoxycytidine treatment of a highly metastatic cell line showed demethylation and re-expression of the hRAB37 gene and coincided with reduced migration. Knockdown of hRAB37 in low metastasis cell line led to a significant increase in cell migration. Our findings demonstrated that hRAB37 small GTPase and acts as a metastasis-related TSG in lung cancer. Promoter/exon1 methylation is the predominant mechanism in down-regulation of the hRAB37, and can serve as a potential prediction biomarker of NSCLC progression.