The binding of different anions to calix[4]pyrrole has been studied by means of molecular dynamics coupled to thermodynamic integration calculations. The effect of different apolar solvents, octafluoro substitution, and the change in binding free energy derived from the presence of cosolute and water traces (the hydrated salt used to introduce the anion in the solution) were examined. Calculations allow us to rationalize the differential binding of ions to calix[4]pyrrole and octafluorocalix[4]pyrrole as well as to predict the behavior in new solvents for which experimental data are not available yet. It is found that both calix[4]pyrrole and octafluorocalix[4]pyrrole have a dramatic preference for F- in the gas phase and pure aprotic solvents, but the situation can change dramatically in protic solvents or in the presence of the hydrated cation which is used as cosolute of the anion. Overall, our results provide interesting clues for a better understanding of the process detected experimentally as "binding".