Swerilactones C (1) and D (2), two novel diastereomeric lactones with an unprecedented 6/6/6/6/6 pentacyclic ring system, were isolated from the traditional Chinese herb Swertia mileensis. Their structures and relative stereochemistry were elucidated on the basis of spectroscopic methods and further confirmed by X-ray single-crystal diffraction analysis. In vitro antihepatitis B virus (HBV) assay on the Hep G 2.2.15 cell line showed that both compounds 1 and 2 exhibited inhibitory activities against the secretion of HBsAg (IC(50) = 1.24 and 2.96 mM, respectively) and HBeAg (IC(50) = 0.77 and 1.47 mM, respectively).