Carboxymethyldextrans (CMD) with a degree of substitution of carboxymethyl groups DS > 0.9 are precursors for the synthesis of derivatized dextrans termed CMDBS, which present heparin‐like biological properties. Syntheses of CMD in water/organic solvent mixtures using monochloroacetic acid (MCA) and strong alkaline conditions allowed to obtain highly substituted CMD with good reproducibility and high yields. The influences of, respectively, individual concentrations of reactants, composition and temperature of reaction medium, and allowed reaction time have been examined. The most favorable conditions for dextran carboxymethylation were obtained with 3.8 M NaOH and a [MCA]/[dextran] ratio of 2.5, allowed to react at 60°C for 90 min, in a reaction medium consisting of a tert‐butanol/water (alternatively isopropanol/water) 85 : 15 (v/v) mixture. A DS of about 1.0 was obtained in one step, as compared to a DS less than 0.6 when using aqueous conditions. Improvements on overall CMD substitution levels (up to DS of 1.47) were achieved by merely repeating the reaction i. e. using the CMD products of the first reaction as substrate in the second.