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Although preliminary evidence available in the literature suggests that isocyanates and their derivatives may have deleterious health effects including immunotoxicity, but molecular mechanisms underlying such an effect have never been addressed. The present study was carried out to assess the immunotoxic response of methyl isocyanate (MIC) on cultured human lymphocytes isolated from healthy human volunteers. Studies were conducted to evaluate both dose\u2010dependent and time\u2010course response (<jats:italic>n<\/jats:italic> = 3), using <jats:italic>N<\/jats:italic>\u2010succinimidyl <jats:italic>N<\/jats:italic>\u2010methylcarbamate, a surrogate chemical substitute to MIC. Evaluation of DNA damage by ataxia telangiectasia mutated (ATM) and \u03b3 H2AX protein phosphorylation states; measure of apoptotic index through annexin\u2010V\/PI assay, apoptotic DNA ladder assay, and mitochondrial depolarization; induction of oxidative stress by CM\u2010H2DCFDA and formation of 8\u2010hydroxy\u20102\u2032 deoxy guanosine; levels of antioxidant defense system enzyme glutathione reductase; and multiplex cytometric bead array analysis to quantify the secreted levels of inflammatory cytokines, interleukin\u20108, interleukin\u20101\u03b2, interleukin\u20106, interleukin\u201010, tumor necrosis factor, and interleukin\u201012p70 parameters were carried out. The results of the study showed a dose\u2010 and time\u2010dependent response, providing evidence to hitherto unknown molecular mechanisms of immunotoxic consequences of isocyanate exposure at a genomic level. We anticipate these data along with other studies reported in the literature would help to design better approaches in risk assessment of occupational and accidental exposure to isocyanates. \u00a9 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:429\u2013440, 2008; Published online in Wiley InterScience (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.interscience.wiley.com\">www.interscience.wiley.com<\/jats:ext-link>). 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