We investigated the effect of organic acids such as mandelic acid (MA) and tartaric acid (TA) on the adsorption behavior of both histidine (His) and propranolol (PPL) onto liposomes. A cationic and heterogeneous liposome prepared using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/sphingomyelin (SM)/3β-[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-Ch) in a ratio of (4/3/3) showed the highest adsorption efficiency of MA and TA independent of chirality, while neutral liposome DOPC/SM/cholesterol = (4/3/3) showed low efficiency. As expected, electrostatic interactions were dominant in MA or TA adsorption onto DOPC/SM/DC-Ch = (4/3/3) liposomes, suggesting that organic acids had adsorbed onto SM/DC-Ch-enriched domains. The adsorption behaviors of organic acids onto DOPC/SM/DC-Ch = (4/3/3) were governed by Langmuir adsorption isotherms. For adsorption, the membrane polarities slightly decreased (i.e., membrane surface was hydrophilic), but no alterations in membrane fluidity were observed. In the presence of organic acids that had been preincubated with DOPC/SM/DC-Ch = (4/3/3), the adsorption of l- and d-His onto those liposomes was examined. Preferential l-His adsorption was dramatically prevented only in the presence of l-MA, suggesting that the adsorption sites for l-His and l-MA on DOPC/SM/DC-Ch = (4/3/3) liposomes are competitive, while those for l-His and d-MA, l-TA, and d-TA are isolated.