We evaluated the prognostic relevance of several clinical and laboratory parameters in 226 Mayo Clinic patients with chronic myelomonocytic leukemia (CMML): 152 (67%) males and median age 71 years. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included anemia, thrombocytopenia, increased levels of white blood cells, absolute neutrophils, absolute monocyte count (AMC), absolute lymphocytes, peripheral blood and bone marrow blasts, and presence of circulating immature myeloid cells (IMCs). Spliceosome component (P= 0.4) and ASXL1 mutations (P= 0.37) had no impact survival. On multivariable analysis, increased AMC (> 10× 10 9/l, relative risk (RR) 2.5, 95% confidence interval (CI) 1.7–3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4–2.7), decreased hemoglobin (< 10 g/dl, RR 1.6, 99% CI 1.2–2.2) and decreased platelet count (< 100× 10 9/l, RR 1.4, 99% CI 1.0–1.9) remained significant. Using these four risk factors, a new prognostic model for overall (high risk, RR 4.4, 95% CI 2.9–6.7; intermediate risk, RR 2.0, 95% CI 1.4–2.9) and leukemia-free survival (high risk, RR 4.9, 95% CI 1.9–12.8; intermediate risk, RR 2.6, 95% CI 1.1–5.9) performed better than other conventional risk models and was validated in an independent cohort of 268 CMML patients.