Four new oxazole-containing compounds, halishigamides A-D (1-4), have been isolated from an Okinawan marine sponge Halichondria sp. and their structures elucidated on the basis of 2D NMR data. Halishigamide A (1) is the first trisoxazole-containing macrolide possessing a primary amino group in the macrolactone ring. As new congeners of halichondramide (7), halishigamide A exhibited potent cytotoxic activity against murine lymphoma L1210 and human epidermoid carcinoma KB cells (IC50 0.0036 and 0.012 µg/mL, respectively) and antifungal activity against Trichophyton mentagrophytes (MIC 0.1 µg/mL). Halishigamides B-D (2-4) had weak cytotoxicity against L1210 (IC50 4.4, 5.2, and 1.1 µg/mL, respectively) and KB cells (IC50 7.5, 6.5, and 1.8 µg/mL, respectively) and modest antifungal activity against T. mentagrophytes (MIC 25, 25, and 6.5 µg/mL, respectively).