The influence of n-octanol additive agent on the retention behavior, the uniformity of the retention mechanism, as well as the quantitative structure-retention relationships (QSRRs) of weak acidic and basic compounds on reversed-phase high performance liquid chromatography (RP-HPLC) was systematically discussed in this paper, especially for the QSRRs of logarithm of apparent n-octanol/water partition coefficient (log K 00 ow ) and logarithm of retention factor extrapolated to neat aqueous mobile phase (log k w(o) ), which have not been discussed in other studies to date. For this purpose, the aqueous fraction of mobile phase was saturated with n-octanol and 0.25% (v/v) n-octanol was added into organic modifier. Eleven substituted benzoic acids, as well as fifteen anilines or pyridines were selected to establish QSRR models by using different types of ion-suppressors. The results indicated that the roles of n-octanol were different in various systems. For acids compounds, if perchloric acid (strong acid) acts as an ion-pair agent, the silanophilic interaction between solutes and residual silanol groups of alkyl-silica stationary phase can be ignored, and n-octanol/water partition and chromatographic process are homoenergetic. In this case, n-octanol acts only as organic modifier. However, if acetic acid (weak acid) or phosphoric acid/potassium dihydrogen phosphate (buffer salt) were used as the ion-suppressor, noctanol is not only an organic modifier, but also a masking agent of free silanols. For weak bases, if ammonium chloride-ammonia was employed as the ion-suppressor, the addition of n-octanol will make QSRRs correlation significantly worse. Therefore, for studying on QSRRs of lipophilicity and retention behavior of acidic and basic compounds, n-octanol is only recommended for acidic system, and strong monoprotic acids, e.g., perchloric acid, are recommended as the ion-suppressors.