Cocaine and its phenyltropane analogs, including 2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane can exist in either the cationic or the neutral form, with the proportion of each form determined by the pKA and ambient pH. It is unknown which form is the active form for binding to the dopamine transporter. Our study examines the following models for the pH dependency of [3H]2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane binding to the dopamine transporter in rat striatal membranes: 1) pH does not affect the binding affinity of the ligand for the dopamine transporter, and the observed binding is a function only of the concentration of the active form; and 2) pH affects the binding affinity of the ligand for the transporter, and changes in this affinity as well as in the concentration of the active form of the ligand in the medium contribute to the observed binding changes upon varying pH. For each model, predictions are formulated for the case that either the cation, neutral base, or both are the active form, and these predictions are compared with the experimental data obtained over a pH range of 6 to 9.5. Observations for 2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane, which can be both in the cationic and neutral form, are compared with those for cocaine methiodide, which is permanently cationic, and benzocaine, which is permanently neutral. Consonant with all data is a simple model in which the cationic and neutral form have similar binding activity and binding changes as a function of pH are caused by changes at the level of the transporter rather than the ligand.