<jats:title>Abstract</jats:title><jats:p>A highly oxygenated hexacyclic indole alkaloid, penicamedine A (<jats:bold>1</jats:bold>), bearing a rare furan ring, was isolated from the culture broth of <jats:italic>Penicillium camemberti</jats:italic>, together with two known analogs, iso‐<jats:italic>α</jats:italic>‐cyclopiazonic acid (<jats:bold>2</jats:bold>) and cyclopiazonic acid (<jats:bold>3</jats:bold>). The structure of <jats:bold>1</jats:bold> was elucidated by comprehensive spectroscopic analyses including NMR and HR‐ESI‐MS. Its absolute configuration was further confirmed unambiguously by single‐crystal X‐ray diffraction analysis. Compound <jats:bold>1</jats:bold> was evaluated for anti‐HIV activity with p24 assays and tested for cytotoxic activities against five human cancer cell lines, including HL‐60, SMMC‐7721, A‐549, MCF‐7, SW480, and the immortalized non‐cancerous human pulmonary epithelial cell line BEAS‐2B by MTS method.