A series of 1H-isochromen-1-ones and their thio analogues (1H-isochromen-1-thione) has been considered for evaluation of their cytotoxic effect on the H460 cancer cells by a propidium iodide assay. A quantitative structure-activity relationship has been developed between the cytotoxicity against H460 (at 0.1 μM) and the structural features of the compounds. Statistical measures such as r2 (0.86), q2 (0.58), pred-r2 (0.94), and F-ratio (15.22) were found to be in an acceptable range. © 2016 by Apple Academic Press, Inc.