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Purpose: In this study, we evaluated Sideritis stricta (S. stricta), as potential-oxidative agents against parental and epirubicin-HCl resistant H1299 cells. Material and Methods: Oxidative stress biomarkers such as malondialdehyde level determined in cell lysates. Assessment of cell viability was made by CellTiter-Blue® Cell Viability Assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5- diphenyl-2H-tetrazoliumbromide (MTT) assay after 20-600 µg/mL essential oil concentrations treated to parental and epirubicin-HCl (drug) resistant H1299 cells for 24, 48 and 72 h. Malondialdehyde levels were assayed for determining the membrane damaging effects. Results: Parental H1299 cells were found to be more sensitive to cytotoxic effect of the essential oil. Essential oil showed cytotoxic and more selective effects depend on time and concentration. Essential oil caused increasing malondialdehyde level on both parental and drug resistant H1299 cells. The highest concentration of the essential oil (IC70) treatment caused the highest membrane damage on both parental and drug resistant H1299 cells. Conclusions: Parental and epirubicin-HCl resistant H1299 cells showed different cellular response against potential antitumour and pro-oxidative effects of essential oil. [ABSTRACT FROM AUTHOR]