Abstract: The series of fifteen lipophilic 2-aryl-5,7-di-tert-butylbenzoxazoles substituted in the phenyl ring was prepared by the reaction of 2-amino-4,6-di-tert-butylphenol with the appropriated aldehydes. The general synthetic approach of all newly synthesized compounds is presented. All the substituted 5,7-di-tert-butylbenzoxazole 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 log P data calculated in various ways is shown. The relationships between the lipophilicity and the chemical structure of the studied compounds are discussed as well.