Novel scalarane sesterterpenes (1-4) were isolated from a sponge, Hyrtios erecta (order Dictyoceratida). They were characterized by means of spectral analyses, X-ray crystallography, and chemical reactions. Compound 1 showed potent in vitro and in vivo antitumor activities. In addition, the structure-activity relationship was also discussed using computer-assisted structure matching of 1 and aragusterols.