The cyanobacteria-containing Caribbean sponge, Calyx cf. podatypa, was collected from three sites in the Bahamas. In each of the three collections, a polar solvent partition fraction contained six known compounds including five diketopiperazines [1-4,6] and phenylacetic acid, along with a new diketopiperazine, cyclo-(4-methyl-R-proline-S-norvaline) [5]. Interestingly, all six diketopiperazines are proline-derived cyclic dipeptides. This is the first example for this class of peptide derivative to be isolated from a Calyx sponge. Parallel studies of one of the sponge collections in which the ectosome (cyanobacteria-rich) was separated from the endosome (no cyanobacteria) revealed no significant differences in their content of diketopiperazines.