The macrocyclic lathyrane polyester Euphorbia factor L10 (1a) has been obtained from the seeds of the caper spurge (E. lathyris). The interaction of L10 (1a) and its acetyl derivative (1b) with P-glycoprotein, a multidrug transporter overexpressed in cancer cells and responsible for resistance to chemotherapy, was investigated. The results established lathyrane diterpenoids as a novel chemotype for P-glycoprotein inhibitors.