Five new steroidal alkaloids, plakinamines C (1) and D (2), and the related compounds 3–5 have been isolated from the Vanuatu sponge Corticium sp. Their structures have been elucidated by a detailed spectroscopic analysis, including 2D-HMBC and ROESY correlation experiments. The new compounds show significant in vitro cytotoxicity against human bronchopulmonary non-small-cell lung carcinoma cells (NSCLC-N6) with IC50 values of 3.3–5.7 µg/mL. When tested against T leukemia virus type one (HTLV-I), compounds 1, 4 and 5 were found to exhibit slight anti-HIV activity.