<jats:title>Abstract</jats:title><jats:p>Two new oxepine‐containing diketopiperazine‐type alkaloids, varioloids A and B (<jats:bold>1</jats:bold> and <jats:bold>2</jats:bold>, resp.), were isolated from the algal‐derived fungus <jats:italic>Paecilomyces variotii</jats:italic> 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 <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> exhibited potent activity against the plant‐pathogenic fungus <jats:italic>Fusarium graminearum</jats:italic> with <jats:italic>MIC</jats:italic> values of 8 and 4 μg/ml, respectively.