The malignancy of non–small cell lung cancer (NSCLC) largely results from its invasive manner. Secreted frizzled-related proteins (SFRPs) have been recently found to suppress the invasiveness of some cancers. On the other hand, the methylation of SFRPs increases protein degradation to reduce the activity of SFRPs, resulting in increased tumor cell invasion and cancer metastasis. However, the role of SFRPs in the invasion of NSCLC has not been reported. Here we analyzed the regulation of SFRPs in NSCLC cells and its effects on cell invasion. We found that SFRP2 mRNA was significantly decreased and methylation of SFRP2 gene was significantly increased in NSCLC tissue, compared to the paired adjacent nontumor tissue. Moreover, SFRP2 expression was significantly decreased in NSCLC cell lines. In NSCLC cell lines, the SFRP2 expression would be restored by the demethylation of SFRP2 gene with 5′-aza-deoxycytidine in NSCLC cell lines, at the levels of both mRNA and protein. Thus, the cell invasion would be suppressed. Furthermore, the demethylation of SFRP2 gene appeared to inhibit Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and matrix metallopeptidase 9 (MMP9), two key factors that enhance NSCLC cell invasion. Thus, SFRP2 may inhibit NSCLC invasion by suppressing ZEB1 and MMP9, while its methylation promotes NSCLC invasion.