Drug-induced phospholipidosis (PLD) is an excessive accumulation of polar phospholipids within cells as a result of medical treatment. Even though a direct link between in vitro drug-induced PLD and toxicity in humans has not yet been firmly established, the development of PLD during preclinical testing in animals is a recognized problem in the pharmaceutical industry and can delay or abort the development process. Therefore, it is of interest to investigate the potential PLD risk of candidates at an early stage of the drug discovery process. In this work, a high throughput physicochemical approach, which is based on measuring the retention factors of the test compound within several different separation systems, was developed for screening phospholipidosis-inducing potential (PLIP) of pharmaceuticals. The measured retention factors of 36 drugs were compared with literature data on PLIP risk from three different sources. It is clearly shown that there is a statistical correlation between the chromatographic retention parameters of tested drugs and their PLIP risk. In conclusion, the retention factor (logk(AOT)) observed on a docusate sodium salt (AOT) surfactant vesicle electrokinetic chromatography (EKC) system and the logarithm of the volume of distribution (logV(d)) calculated from immobilized artificial membrane chromatography at pH 7.4 (CHI IAM(7.4)) and HSA binding value (% HSA) can provide primary profile prediction for a large number of drug candidates early in the drug discovery process with minimal resources. The observations are that the higher the value of both logk(AOT) and logV(d), the higher the PLIP risk, and we would recommend this dual approach.