Purpose: To investigate the effect of personalized sweat sodium replacement on drinking behavior, sodium and water balance, and thermophysiological responses during and after ultraendurance running in hot conditions. Methods: Nine participants (7 male, 2 female) completed two 5-hour treadmill runs (60% maximum oxygen uptake, 30°C ambient temperature), in a double-blind randomized crossover design, consuming sodium chloride (SODIUM) capsules to replace 100% of previously assessed losses or placebo (PLACEBO). Fluid was consumed ad libitum. Results: No effect of SODIUM was observed for ad libitum fluid intake or net fluid balance (P > .05). Plasma sodium concentration increased in both trials, but to a greater extent in SODIUM at 2.5 hours (mean [SD]: 4 [4] mmol·L−1 vs 1 [5] mmol·L−1; P < .05) and postexercise (4 [3] mmol·L−1 vs 1 [5] mmol·L−1; P < .05). Plasma volume change was not different between trials (P > .05) but was strongly correlated with sodium balance in SODIUM (r = .880, P < .01). No effect of sodium replacement was observed for heart rate, rectal temperature, thermal comfort, perceived exertion, or physiological strain index. During the 24 hours postexercise, ad libitum fluid intake was greater following SODIUM (2541 [711] mL vs 1998 [727] mL; P = .04), as was urinary sodium excretion (NaCl: 66 [35] mmol, Pl: 21 [12] mmol; P < .01). Conclusions: Personalized sweat sodium replacement during ultraendurance running in hot conditions, with ad libitum fluid intake, exacerbated the rise in plasma sodium concentration compared to no sodium replacement but did not substantially influence overall body-water balance or thermophysiological strain. A large sodium deficit incurred during exercise leads to substantial renal sodium conservation postexercise.