BACKGROUND: Because of its high demand for use in pharmaceutical products, cosmetics, soil remediation technologies, etc., randomly methylated beta-cyclodextrin (RM-beta-CD) is one of the most important cyclodextrin (CD) derivatives. The aim of this present work is to use a green and commercially available approach to obtain RM-beta-CD. Compared with other methylated CDs, RM-beta-CD with an asymmetric molecular structure has higher water solubility. When the degree of substitution (DS) is about 1.8, the solubility tends to increase with increasing temperature and is suitable for pharmaceutical applications. RESULTS: RM-beta-CD was synthesized using a green approach with ideal DS equal to 1.79. The one step process of beta-cyclodextrin methylation by CH3Cl instead of (CH3)(2)SO4 at mild temperature (80 degrees C) and pressure (1.60 MPa) with a good yield (78%), is convenient and environmentally friendly. The mixture of RM-beta-CD obtained contained five compounds with various DS, from which the main compound with a DS equal to 1.8 was separated by column chromatography. The compounds were carefully characterized by infra-red, NMR and mass spectrometry. CONCLUSIONS: The one-step process to RM-beta-CDs with CH3Cl is more economical, more efficient and less noxious than the usual method using (CH3)(2)SO4. Moreover, this approach avoids some poisonous residual materials and meets the demand for protecting the environment. (C) 2009 Society of Chemical Industry