In our continuing program to identify bioactive compounds from marine invertebrates, the MeOH-EtOAc (1:1) extract of the sponge Plakortis aff simplex, collected in Madagascar, was found to be cytotoxic to a series of human tumor cells. From this sponge, three new compounds and one known one, two new 1,2-dioxane peroxylactones named plakortolides H (1) and I (2), and one new 1,2-dioxolane, designated andavadoic acid (3), have been isolated and their structures elucidated. In addition, the known N(3)-methyladenine (4) was isolated, to the best of our knowledge, for the first time from a marine source. Andavadoic acid (3) showed significant activity against 13 tumor cells with GI(50) values in the submicromolar range.