The files provided in this U.S. Geological Survey (USGS) data release (Kellogg and others, 2021) include an amplicon sequence variant (ASV) table and the raw 16S rRNA gene amplicon files from six microbial communities (Mcav17, Mcav18, McH-101, McH-103, McD-57, and McD-58) derived from mesocosms consisting of filtered seawater in which either healthy or diseased (stony coral tissue loss disease) fragments of Montastraea cavernosa had been incubated, as well as sequence files of a mock community and extraction kit blank. Mesocosms were inoculated at the Smithsonian Marine Station located in Fort Pierce, Florida, during two separate trips: one in October 2019 and the other in November 2020. The coral fragments were collected between April 2018 and November 2020, from various locations throughout the Florida Keys. Mesocosms were set up by placing the coral fragments into filtered seawater for 4-5 days and then the fragments were removed so the water could be processed. The mock community was sequenced to assess any biases in the sequencing technology, while extraction blanks were sequenced to identify any contaminants in the DNA extraction kit.