Black band disease (BBD), a lethal, polymicrobial disease consortium dominated by the cyanobacterium Roseofilum reptotaenium, kills many species of corals worldwide. To uncover chemical signals or cytotoxins that could be important in proliferation of Roseofilum and the BBD layer, we examined the secondary metabolites present in geographically diverse collections of BBD from Caribbean and Pacific coral reefs. Looekeyolide A (1), a 20-membered macrocyclic compound formed by a 16-carbon polyketide chain, 2-deamino-2-hydroxymethionine, and d-leucine, and its autoxidation product looekeyolide B (2) were extracted as major compounds (∼1 mg g-1 dry wt) from more than a dozen field-collected BBD samples. Looekeyolides A and B were also produced by a nonaxenic R. reptotaenium culture under laboratory conditions at similar concentrations. R. reptotaenium genomes that were constructed from four different metagenomic data sets contained a unique nonribosomal peptide/polyketide biosynthetic cluster that is likely responsible for the biosynthesis of the looekeyolides. Looekeyolide A, which readily oxidizes to looekeyolide B, may play a biological role in reducing H2O2 and other reactive oxygen species that could occur in the BBD layer as it overgrows and destroys coral tissue.