Water depleted of heavy isotopes, such as 2H1 and 18O16 (HIDW), has shown numerous biological/health effects in vitro, in vivo, and in epidemiological studies. Major observations were related to cell growth/differentiation, immune/nervous system responses, endurance/adaptation, mitochondrial electron transfer, energy production, glucose metabolism, etc. No human studies to confirm physiological, metabolic, and immune responses to the consumption of HIDW have been performed. A placebo-controlled study on healthy volunteers (n = 50) under fitness load who consumed 1.5 L HIDW (58 ppm 2H and 1780 ppm 18O) or normal water for 60 days was carried out. Plasma content of 2H1 and 18O16, markers of energy, lipid, and glucose metabolism, anthropometric, cardio-vascular, oxidant/antioxidant, and immunological parameters were determined. Significant decrease in plasma heavy isotopes in the group consuming HIDW was observed in concomitance with an increase in ATP, insulin, and LDH, and diminished plasma lactate. Several anthropometric and cardio-vascular parameters were improved as compared to placebo group. Lipid markers demonstrated antiatherogenic effects, while oxidant/antioxidant parameters revealed HIDW-induced hormesis. Antibacterial/antiviral immunity was remarkably higher in HIDW versus placebo group. Conclusions: HIDW consumption by humans under fitness load could be a valid approach to improve their adaptation/recovery through several mechanisms.