In reversed phase liquid chromatography (RP-LC), the validity of a multiparametric (MP) non-linear least-squares regression iterative method has been evaluated for 14 different aqueous mobile phases modified with one, two or three organic solvents [acetonitrile (ACN), methanol (MeOH), or tetrahydrofuran (THF)] for calculating the retention time of unretained compound tM and the regression parameter (slope b), based on the use of alkan-2-ones and alkyl aryl ketones homologous series. The determination of tM and b has been studied for eight binary (ACN–H2O or MeOH–H2O), 3 ternary (ACN–MeOH–H2O) and 3 quaternary (ACN–MeOH–THF–H2O) mobile phase systems on an Omnispher C18 column. The multiparametric calculated tM and b values were compared with those obtained by Guardino’s, and Grobler’s methods. The MP retention indices (RI) of ten monosubstituted benzenes with different functionality (hydroxyl, carbonyl, nitro, etc.) based on the alkan-2-ones retention index standards have been determined and compared for the different mobile phase compositions studied. The influence of organic modifier type, the nature of mobile phase system and water content on the variation of retention parameter studied in this work were discussed.