The invention relates to synthesis of hydrocortisone butyrate, which comprises the following steps of: A. carrying out acylation reaction on hydrocortisone acetate adopted as a raw material and butyl chloride in an organic solvent I under the condition of existence of a catalyst; after the reaction is finished, adding acid to adjust a pH value being smaller than 5; diluting or recrystallizing to obtain hydrocortisone 17alpha-butyrate-21-acetate; and B. adopting the hydrocortisone 17alpha-butyrate-21-acetate as a raw material, adding inorganic alkali in an organic solvent II and carrying out selective hydrolysis reaction to obtain hydrocortisone 17alpha-butyrate.