Phospholipidosis (PLD) is a lysosomal storage disorder induced by compounds, notably cationic amphiphilic drugs, which although reversible interferes with cellular phospholipids.The in silico method described utilizes the amphiphilic moment ΔΔG(AM) (kJ/mol) together with basic pK(a) values to assign PLD inducing potential to a compound. The new model was accurate and sensitive (85% and 82%, respectively) when compared to other data sets. Therefore, the parallel in vitro assay for PLD was discontinued. The data reinforce our view that the amphiphilic moment is far more informative for determining a compound's potential to induce PLD than the combined use of basic pK(a) and ClogP values.