Bioassay-guided fractionation provided conocurvone (l), a novel trimeric naphthoquinone derivative, as the active anti-HIV constituent of an extract from a Conospermum sp. The related naphthoquinone monomer teretifolione B (2) also was isolated from a Conospermum sp. extract. The absolute stereochemistry of 2 was established by X-ray crystallographic analysis of the p-bromobenzoate derivative 6. Base-catalyzed coupling of 2 equiv of teretifolione B (2) with the deoxy derivative 8 provided compound 1, which was identical in all respects with the natural product. While compound 2 was inactive against HIV, the natural and synthetic conocurvone (1) and the synthetic trimeric analog 4 were all active and equipotent, preventing the cytopathic effects and replication of HIV in human T-lymphoblastic cells (CEM-SS) over a concentration range of 0.02-50 pM.