We compared five regression approaches, namely, ordinary least squares, major axis, reduced major axis, robust, and Prais–Winsten to estimate δ18O-δ2H relationships in four water types (precipitation, surface water, groundwater collected in wells from lowlands, and groundwater from low-yield springs) from the northern Italian Apennines. Differences in terms of slopes and intercepts of the different regressions were quantified and investigated by means of univariate, bivariate, and multivariate statistical analyses. We found that magnitudes of such differences were significant for water types surface water and groundwater (both in the case of wells and springs), and were related to robustness of regressions (i.e., standard deviations of the estimates and sensitiveness to outliers). With reference to surface water, we found the young water fraction was significant in inducing changes of slopes and intercepts, leading us to suppose a certain role of kinetic fractionation processes as well (i.e., modification of former water isotopes from both snow cover in the upper part of the catchments and precipitation linked to pre-infiltrative evaporation and evapotranspiration processes). As final remarks, due to the usefulness of δ18O–δ2H relationships in hydrological and hydrogeological studies, we provide some recommendations that should be followed when assessing the abovementioned water types from the northern Italian Apennines.