Objective Invasive lung tumors are associated with intercellular adhesion molecule-1 (ICAM-1) expression. Secretory phospholipase A2 (sPLA2 ) enzymes produce inflammatory mediators that stimulate ICAM-1 expression, and upregulation of PLA2 activity can enhance metastasis. We hypothesize a link between sPLA2 activity, ICAM-1 expression, and tumor cell invasion. We propose that inhibition of sPLA2 modulates ICAM-1 expression in cancer cells and attenuates their invasiveness. Methods Human lung adenocarcinoma cells (A549) were treated with an ICAM-1 blocking antibody and assayed for invasion. Lung cancer cells (A549 and H358) were then treated with an sPLA2 inhibitor and evaluated by immunoblotting for ICAM-1 expression. Next cells (A549) treated with sPLA2 inhibitor were assayed for invasion. Finally, sPLA2 messenger RNA and protein expression were evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence microscopy, respectively. Statistical analysis was performed by the Student t test or analysis of variance, as appropriate. Results Antibody blockade of ICAM-1 decreased lung cancer cell invasion. sPLA2 inhibition significantly reduced ICAM-1 expression and invasion. sPLA2 inhibition also significantly decreased sPLA2 mRNA expression and immunofluorescent staining of sPLA2. Conclusions sPLA2 plays a significant role in mediating the inflammatory signals that induce ICAM-1 expression in lung cancer cells. Inhibition of the enzyme can significantly decrease ICAM-1 expression and subsequent cancer cell invasion. This lays the groundwork for further investigation into the cellular mechanisms of sPLA2 and its role in lung cancer.