Twelve new (1-7, 9-13) polyhydroxysterols and two new saponins (14 and 15) were isolated from the starfish Certonardoa semiregularis by activity-guided fractionation. Compounds 1-7 are rare examples of 15-keto steroids from starfish. The side chain of compound 11 was also unprecedented in nature. The structures were determined by combined spectroscopic methods and chemical derivatization. These compounds were evaluated for cytotoxicity against a small panel of human solid tumor cell lines, and most of them exhibited considerable activity. One of the 15-keto sterols (6) displayed the highest potency, which is comparable to that of doxorubicin.