Two unique sesterterpenes, hyattellactones A (1) and B (2), together with two known sesterterpenes, phyllofolactones F (3) and G (4), were isolated from the Indonesian marine sponge Hyattella sp. The structures of the two new compounds, 1 and 2 were assigned based on their spectroscopic data. Hyattellactone A (1) was a scalarane sesterterpene with an α,β-unsaturated-γ-lactone ring and C-ethyl group, while B (2) was an epimer of 1 at the C-24 position. Compounds 1 and 3 inhibited PTP1B activity with IC50 values of 7.45 and 7.47μM, respectively. On the other hand, compounds 2 and 4 (24S-isomers of 1 and 3, respectively) showed much reduced activity than the 24R-isomers.