Abstract: The present invention is directed to methods of treating sickle cell disease and its sequelae, including vaso-occlusive crisis. The method comprises administering to a subject in need thereof a pharmaceutical composition comprising an elective amount of a polyanionic polysaccharide, such as pentosan sulfate, sulodexide, or its pharmaceutically acceptable salts thereof. The methods of the present invention are useful in reducing the incidence, severity, or duration of SCD and its sequelae. The compound of the present method can also be used in conjunction with other therapeutic agents useful to treat sickle cell disease thus enhancing the therapeutic elect of reducing the required dosed to treat sickle cell disease.