Sponges are fundamental components of coral reef communities and, unfortunately, like other major benthic members, they too have been impacted by epizootic and panzootic events. We report on the prevalence of disease-like conditions affecting populations of the giant barrel sponge Xestospongia muta across shallow and mesophotic coral reefs off La Parguera Natural Reserve (LPNR) and Mona Island Marine Reserve (MIMR) in Puerto Rico. Four different conditions affecting X. muta were observed during our surveys, of which 3 have been previously reported: cyclic spotted bleaching (CSB; apparently non-lethal), Xestospongia-tissue wasting disease (X-TWD; apparently lethal), and sponge orange band disease (SOB; sparsely associated with X-TWD infected individuals). Additionally, we describe a fourth condition, Xestospongia-tissue hardening condition (X-THC), a previously unreported disease recently observed along the insular shelf margin off LPNR and MIMR. Within LPNR, a total of 764 specimens of X. muta were inspected and measured. Of these, 590 sponges (72.2%) had CSB, 25 (3.27%) had signs of X-TWD, 7 (0.92%) had SOB, and the remaining 142 (18.6%) were apparently healthy. Three colonies inhabiting upper mesophotic depths on the LPNR insular shelf showed signs of CSB and X-TWD. At MIMR, video-transect surveys revealed a total of 514 colonies, of which 40 (7.78%) had signs of CSB and/or XTWD, 14 (2.72%) were affected by X-THC, while the remaining 460 (89.5%) showed no external signs of disease and appeared healthy. The presence of 4 concomitant disease-like conditions in barrel sponges of Puerto Rico is alarming, and indicative of the deteriorating status of Caribbean coral reefs.