A computer program (DryLab MP®) is described for the simulation of HPLC separations where two or more variables (e.g., temperature and pH) are changed simultaneously. It is assumed that preliminary method development has resulted in a mobile phase of appropriate strength, such that 1 < k′ < 20 for all bands in the chromatogram. If it is desired to simulate separation as a function of changes in the values of n variables, then one or two additional runs are carried out for each variable —changing only that variable. Retention times for each of the latter runs are entered into the computer, and predictions of separation as a function of all conditions are now possible. Because simultaneous changes in two or more variables can lead to significant interaction effects and less accurate predictions, the software evaluates each simulation for possible errors. Allowed conditions must be capable of predicting values of α with an accuracy better than ± 2% (1 S.D.). The present computer program has a number of possible applications during and following method development, as discussed in the following paper (Part II).