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Purpose: Cancer-initiating cells (CICs) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for high recurrence rates and low responses to chemotherapy.This study is aimed at investigating and characterizing a novel candidate stemness-maintaining molecule, galectin-3, in mediating stemness properties of lung cancer cells.Methods: We enriched H 1299 lung cancer-initiating cells (H 1299-CICs) though sphere formation within defined serum-free medium.Differential expression profile of stemness genes between enriched H 1299-CICs and parental H1299 cells was elucidated.The role of galectin-3 in mediating stemness properties was evaluated by shRNA-delivered knockdown of galectin-3.Sphere forming efficiency and tumorigenicity such as invasion and colony formation in soft agar were examined.Results: Enriched H1299-CICs highly expressed the stem/Progenitor cell markers such as Oct-4, SOX-2 and Nanog.The expression of galectin-3 was robustly increased in primary and secondary spheres.Upon suppression of galectin3 in either parental H1299 or H1299-CICs, sphere forming ability and tumorigenicity were significantly decreased.To examine a novel molecular mechanisms regulated by galectin-3 in maintaining the stemness properties, protein microarrays were performed.We found that protein levels of GM-CSF were increased in H 1299-CICs and decreased in galecitin-3-irnhibited cells.Conclusion: Our finding revealed a role for galectin-3 in maintaining the stemness properties and tumorigenicity of lung CICs, suggesting that targeting galectin-3 signaling may provide a new strategy for lung cancer treatment by eliminating cancer stem-like cells.