Luffariolides F [1] and G [2], two new manoalide-related sesterterpenes with cytotoxic activities, have been isolated from the Okinawan marine sponge Luffariella sp. and their structures elucidated on the basis of spectroscopic data. Manoalide (1) and related sesterterpenes (2-5) have been extensively investigated because of their potent antiinflammatory activity and irreversible inhibition of phospholipase A2 (6-10). We previously studied a sponge of the genus Luffariella (family Thorectidae; order Dictyoceratida) and isolated five new cytotoxic sesterterpenes, luffariolides A-E (11). Here we describe the isolation and structure elucidation of two other structurally related sesterterpenes, luffariolides F [1] and G [2], both possessing cytotoxic activity, from a different collection of Luffariella sp.