Novel epidithiodioxopiperazines, emethallicins E (1) and F (2), were isolated from the mycelial extract of Emericella heterothallica (mating type A). The structures of emethallicins E (1) and F (2) were determined on the basis of spectroscopic and chemical investigation, compared with other emethallicins isolated from the above fungus and the other strain. Emethallicin E (1) is an epidithiodioxopiperazine having a novel carbon skeleton related to emethallicins A (3), B (4), C (5), and D (6), whereas emethallicin F (2) has the same carbon skeleton as emethallicins A (3), B (4), and D (6). Emethallicins E (1) and F (2) have a potent inhibitory activity for histamine release as well as the other emethallicins.