The giant barrel sponge, Xestospongia muta represents a foundation and ecologically important species of Caribbean coral reefs. In April 2012 an outbreak of Sponge Orange Band (SOB) Disease occurred in Southeast Florida, USA. This study provides one of the most extensive profiles of healthy and SOB-associated microbial communities within Xestospongia muta to date with implications of a possible polymicrobial origin for SOB.