Two new oxepine-containing diketopiperazine-type alkaloids, varioloids A and B (1 and 2, resp.), were isolated from the algal-derived fungus Paecilomyces variotii EN-291. The structures and absolute configurations were determined by detailed interpretation of 1D- and 2D-NMR spectroscopic data and by analysis of acidic hydrolysates. Compounds 1 and 2 exhibited potent activity against the plant-pathogenic fungus Fusarium graminearum with MIC values of 8 and 4 mu g/ml, respectively.