The bioassay-guided fractionation of the crude extract of the marine sponge Axinella weltneri led to the isolation and the identification of a new triterpene named sodwanone S (1), with an uncommon oxepane-cyclohexane system, along with the known sodwanones A and G. The structure was elucidated using spectroscopic data, and the biological activity was evaluated against 13 human tumor cell lines. A biogenetic pathway of this new compound is also proposed.