An extensive search for the trisoxazole macrolides in the Thai specimen of the sponge Pachastrissa nux led to the isolation of a new kabiramide derivative, kabiramide L (1) and the previously reported kabiramide I (2). Both macrolides had a moderate antiplasmodial activity against Plasmodium falciparum K1 with IC50s of 2.6 and 4.5 µM, respectively. To date, P. nux has been the only known source of the trisoxazole macrolides bearing the 30-enone moiety. Both compounds were also added to the list of chemicals postulated to play a defensive role in the P. nux sponge.