Evolution in preparation of chromatographic columns has created the need for studying and evaluating them with the use of smart software. This research is an attempt to compare the retention mechanism between two stationary phases (butyl and phenyl) with the use of multivariate analysis for a large number of probes. Partial least squares has the ability to spot either major or minor differences in the chromatographic behavior of probes, with regard to changes in the stationary or mobile phases. The models developed refer to a total of 108 miscellaneous chemical compounds, described by 63 X variables (physicochemical properties and structural features) and one Y variable (retention time). The results showed that in both columns and mobile phases (40% methanol or 40% acetonitrile) the retention of an analyte is mainly affected by its lipophilicity, molar volume, and refractivity, which tend to cause delayed elution. On the contrary, solubility in water, polar surface area, and hydrogen bond donor or acceptor properties promote faster elution. The most important difference proved to be the effect of the presence of the carboxylic group and the solubility that affected the retention in a similar way in both columns but not with both mobile phases.