Abstract: A series of fourteen lipophilic 2-substituted 5,7-di-tert-butylbenzoxazoles was prepared by the reaction of 2-amino-4,6-di-tert-butylphenol with appropriated aldehydes. The general synthetic approach of all newly synthesized compounds is presented. All the substituted 5,7-di-tert-butylbenzoxazoles derivatives were analyzed using the reversed phase high performance liquid chromatography (RP-HPLC) method for the lipophilicity measurement. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using end-capped non-polar C18 stationary RP column. In the present study the correlation between RP-HPLC retention parameter Log K (the logarithm of capacity factor K) and various calculated Log P values is shown. The relationships between the lipophilicity and the chemical structure of the studied compounds are discussed as well.