Two new sesquiterpene gamma-methoxybutenolides, hyrtiosenolides A (1) and B (2), together with a new 4alpha-methyl polyoxygenated steroid, hyrtiosterol (3), were isolated from a Red Sea sponge, Hyrtios species. Their structures were elucidated by analysis of their 1D and 2D NMR spectra and HRFABMS. Compounds 1 and 2 showed weak antibacterial activity against Escherichia coli.