Background: Comorbidities significantly affect the prognosis and outcomes of patients with hematological malignancies. We have previously reported the impact of comorbidities on the IPSS score. The aim of this study was to determine whether comorbidities continued to have a significant impact when patients were reclassified according to the Revised-International Prognostic Scoring System (IPSS-R). Methods: The medical records of 600 consecutive MDS patients who presented to MD Anderson Cancer Center between January 2002 and June 2004 were reviewed. The Adult Comorbidity Evaluation-27 (ACE-27) was used to assess the severity of comorbid conditions. Results: Four hundred and two (67%) patients were male. Median age at presentation was 66.6 years (17 - 94). Mean duration of follow-up was 54 months (1 - 100). Five hundred and two (84%) patients died, and 54 (9%) patients underwent SCT. Overall median survival was 16.8 months (1 - 100). Median survival by IPSS-R was 47, 34, 21, 16, and 6 months for patients in very low, low, intermediate, high and very high-risk groups, respectively (P<0.001). The ACE-27 comorbidity score significantly impacted the median survival of patients in the intermediate (P<0.001), high (P=0.045), and very high (P=0.004) IPSS-R groups; but did not significantly impact the median survival in the low (P=0.11) and very low (P=0.49) IPSS-R groups. The ACE-27 comorbidity score significantly impacted the median survival of patients ≤ 65 years (P<0.001) but did not significantly impact those > 65 years (P=0.18). Conclusion: Assessment of comorbidity may enhance the prognostic ability of the IPSS-R.