Two new epidithiodiketopiperazines, pretrichodermamide C (1) and N-methylpretrichodermamide B (2) were isolated from the fungus Penicillium sp., derived from the sediment of a hyper saline lake located at Wadi El-Natrun in Egypt. The structures of 1 and 2 were unambiguously determined on the basis of one-and two-dimensional NMR spectroscopy and by high-resolution mass spectrometry, as well as by comparison with the literature. Compound 2 showed pronounced cytotoxicity against the murine lymphoma L5178Y cell line with an IC50 value of 2 mu M. (C) 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.