Quantitative structure-retention relationship (QSRR) was developed for a series of the (Z)- and (E)-2-alkylidene-4-oxothiazolidine derivatives by the multiple linear regression (MLR) analysis. Full geometry optimization based on Austin Model 1 (AM1) semiempirical molecular orbital method was carried out and a set of physicochemical molecular descriptors was calculated from the optimized structures. In order to obtain useful experimental parameters, the lipophilic character of analytes was measured by RP-TLC, and lipophilicity parameters were correlated with physicochemical structural descriptors. Statistically significant and physically meaningful structure-retention relationships were obtained.