Liquid-liquid (L-L) phase splitting in mixtures of water (H/D) + 3-methylpyridine (3-MP) at the limit of pure H2O as solvent and under high tension are reported for the first time. The phase diagram is thus encountered at large absolute negative pressure regimes. To the best of the authors' knowledge, these studies constitute the first to report phase transitions in nonpolymeric fluid mixtures at negative pressures, and the values of tension achieved (≈-350 bar) constitute a record for macroscopically sized samples. The overall behavior of mixtures of water (H/D) + 3-MP is successfully interpreted by using a simple gE-model. It is clearly shown that there is an intimate relation between pressures and the isotopic content of the solvent, and, thus, the latter can act as a thermodynamic variable. At critical concentrations, while mixtures of D 2O + 3-MP always present phase separation irrespective of the applied pressure, when the solvent is pure H2O a miscibility window with the size of 1600 bar emerges. This phenomenon corresponds to an impressive pressure shift of several hundred atmospheres upon (H/D) solvent isotopic substitution. When this effect is projected onto the temperature-solvent isotopic content at atmospheric pressure, a 70 K immiscibility loop is encountered when D2O acts as the solvent, while total miscibility occurs for concentrations of D2O (in D2O + H2O) lower than 17 wt %. It is shown that an entropic effect originated at the relatively large difference in molar volumes between water and 3-MP is responsible for the location of the L-L phase diagram in the low-concentration region of 3-MP. It is again another (but subtle) entropic effect that provokes the above-mentioned abnormally large shift in the phase diagram upon isotopic substitution.