OBJECTIVE Grandinin (C(46)H(34)O(30)) is a compound found in Melaleuca quinquenervia leaves and in oaks. This study is to determine effects of grandinin on malignant lung cells and the related molecular mechanisms. METHODS Malignant cells were treated with grandinin with various concentrations. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrozolium bromide (MTT) assays and apoptosis assays were performed to determine effects of grandinin on cell viability and apoptosis. Western blotting and real time-PCR were used to determine if grandinin affects levels of phosphorylated EGFR (p-EGFR) and phosphorylated AKT (p-AKT), as well as their mRNA transcript levels. RESULTS It was found that grandinin treatments reduce viability of malignant lung cells and induces apoptosis. When treated with grandinin (16 μM), the apoptosis of the three lung cancer cell lines MS-1, A549, and LK-2 were increased by 8-9 folds, in comparison with the cells treated with DMSO only (the control condition). Furthermore, grandinin treatments lead to down-regulation of levels of p-EGFR and p-AKT in three malignant lung cell lines. However, grandinin does not affect mRNA levels of EGFR and AKT. CONCLUSIONS These experimental results indicated grandinin significantly reduce malignant cell viability and effectively induces apoptosis of malignant lung cells by mediating phosphorylation down-regulation of cellular signaling proteins EGFR and AKT. It is suggested that grandinin treatments might be an effective therapeutic strategy of lung malignancies upon further studies in the future.