To determine whether burdens of chronic comorbid illnesses can predict the clinical course of prolonged mechanical ventilation (PMV)patients in a long-term, acute-care hospital (LTACH). Retrospective study of 866 consecutive PMV patients whose burdens of chronic comorbid illnesses were quantified using the Cumulative Illness Rating Scale (CIRS). Based on increasing CIRS scores, 6 groups were formed and compared: group A (≤25; n = 97), group B (26-28; n = 105), group C (29-31; n = 181), group D (32-34; n = 208), group E (35-37; n = 173), and group F (>37; n = 102). As CIRS scores increased from group A to group F, rates of weaning success, home discharges, and LTACH survival declined progressively from 74% to 17%, 48% to 0%, and 79% to 21%, respectively (all P < .001). Negative correlations between the mean score of each CIRS group and correspondent outcomes also supported patients' group allocation and an accurate prediction of their clinical course (all P < .01). Long-term survival progressively declined from a median survival time of 38.9 months in group A to 3.2 months in group F (P < .001). Compared to group A, risk of death was 75% greater in group F (P = .03). Noteworthy, PMV patients with CIRS score <25 showed greater ability to recover and a low likelihood of becoming chronically critically ill. Diagnostic accuracy of CIRS to predict likelihood of weaning success, home discharges, both LTACH and long-term survival was good (area under the curves ≥0.71; all P <.001). The burden of chronic comorbid illnesses was a strong prognostic indicator of the clinical course of PMV patients. Patients with lower CIRS values showed greater ability to recover and were less likely to become chronically critically ill. Thus, CIRS can be used to help guide clinicians caring for PMV patients in transfer decisions to and from postacute care setting.