The polyketides dihydroplakortin (3), and the dodecanoic acid derivatives 4 and 5, were isolated from the Caribbean marine sponge Plakortis simplex, and their structures fully characterized by spectroscopic and chemical means. The absolute stereochemistries of the known plakortin (1) and of compounds 3-5 were determined by applying Mosher's and Kusumi's methods on opportune degradation products. The isolated compounds exhibited cytotoxic activity tested in vitro on WEHI 164, murine fibrosarcoma cell line.