Lipophilicity, as an important molecule's property, was analyzed on a series of newly synthesized N-(4-phenylmonosubstituted) cyanoacetamides, by applying the reversed phase thin-layer chromatography (RP-TLC), RP TLC18, in the presence of different organic modifiers in various concentrations (ethanol, n-propanol, acetone and tetrahydrofuran) and by mathematical method, using different software packages. The effect of the chemical structure as well as influence of the applied organic solvents on retention behavior of investigated derivatives was studied. Using different chemometric methods as linear regression analysis, principal component analysis and sum of ranking differences, experimentally determined lipophilicity of investigated compounds (chromatographic retention constant ) was correlated with partition coefficients, log P, as a standard measure of lipophilicity, calculated by applying different computational techniques. The obtained results indicate that all used methods gave approximately similar grouping of the studied lipophilic parameters and demonstrated that the chromatographic retention data are in a good agreement with standard measure of lipophilicity. This fact confirm that chromatographic retention parameter of the investigated N-(4-phenylmonosubstituted) cyanoacetamides obtained by RP-TLC could be used for the description of their lipophilicity.