The absolute content of CD34⁺ cells in the peripheral blood of 84 patients with myelofibrosis with myeloid metaplasia (MMM) and 23 patients with other Philadelphia-negative (Ph⁻) chronic myeloproliferative disorders (CMDs) was investigated. In MMM, the median absolute number of circulating CD34⁺cells was consistently high (91.6 × 10⁶/L; range, 0-2460 × 10⁶/L). Receiver operating characteristic curve analysis showed that 15 × 10⁶/L as a decision criterion for CD34⁺cells produced an almost complete discrimination between MMM patients out of therapy and other Ph⁻ CMDs (positive predictive value, 98.4%; negative predictive value, 85.0%). MMM patients with higher numbers of CD34⁺ cells had a significantly longer disease duration (P = .019) and higher spleen volume index (P = .014), liver volume (P = .000), percentage of circulating immature myeloid cells (P = .020), and percentage of myeloid blasts (P = .000). When CD34⁺ cells were correlated with the use of Dupriez risk stratification, CD34⁺ cells increased significantly from low-risk (median, 68.1 × 10⁶/L) to intermediate-risk (median, 112.8 × 10⁶/L) and high-risk patients (median 666.1 × 10⁶/L) (F = 4.95;P = .009). When CD34⁺ cells were correlated with a severity score on the basis of both myeloproliferative and myelodepletive characteristics of the disease, only the myeloproliferation index was significantly associated with CD34⁺ cell level (F = 5.7;P = .000). Overall survival and interval to blast transformation from the time of CD34⁺ cell analysis were significantly shorter in patients with more than 300 × 10⁶/L CD34⁺ cells (P = .005 and .0005, respectively). In conclusion, the absolute number of CD34⁺ circulating cells allows MMM to be distinguished from other Ph⁻ CMDs; it is strongly associated with the extent of myeloproliferation and predicts evolution toward blast transformation.