Twelve new compounds including four isoflavonolignans (1a/1b and 2a/2b), two neolignans (3a/3b), and six isoflavonoids (5-10), together with seven known compounds (4 and 11-16) were isolated from the stems of Pisonia umbellifera . The structures were elucidated on the basis of comprehensive spectroscopic analyses and ECD calculation methods. Compounds 1-3 were present as enantiomers that were successfully separated by chiral HPLC. Compounds 1a/1b and 2a/2b are the first examples of isoflavonolignans with a pyranoid ring linking up the isoflavonoid and the monolignol from nature. A putative biosynthetic pathway for the isoflavonolignans was deduced. The anti-inflammatory and cytotoxic activities for all compounds were evaluated.