Environmental factors have been implicated in the pathogenesis of neurodegenerative diseases. Maneb (MB) and mancozeb (MZ) have been extensively used as pesticides. Exposure to MB lowers the threshold for dopaminergic damage triggered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. MB and MZ potentiate 1-methyl-4-phenylpyridium (MPP+)-induced cytotoxicity in rat pheochromocytoma (PC12) cells partially via nuclear factor kappa B (NF-κB) activation. RTP801 dramatically increased by oxidative stresses and DNA damage is the possible mechanism of neurotoxins-induced cell death in many studies. This study demonstrated that MB and MZ induced DNA damage as seen in comet assay. The expressions of RTP801 protein and mRNA were elevated after MB and MZ exposures. By knocking down RTP801 using shRNA, we demonstrated that NF-κB activation by MB and MZ was regulated by RTP801 and cell death triggered by MB and MZ was associated with RTP801 elevation. This revealed that the toxic mechanisms of dithiocarbamates are via the cross talk between RTP801 and NF-κB.