Whether the hematopoietic-cell-transplantation-comorbidity-index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given HLA-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades III-IV acute GVHD (p<.0001 and c-statistic of 0.64); and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades III-IV GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1-4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade II (HR=1.24, p<0.0001) or grades III-IV acute GVHD (HR=1.19, p<0.0001). Patients with HCT-CI scores of ≥3 who developed grades II-IV acute GVHD had 2.63 fold higher risk of mortality than those with scores of 0-2 and did not develop acute GVHD. Thus, pre-transplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials.