The controversial debate on the IV use of albumin-containing solutions in patients with severe sepsis or septic shock and, more generally, in critically ill patients, dates back to 1998, when the first high-quality meta-analysis investigating this issue reported a potential increased risk of death associated with the administration of human albumin. After several years of lively debate and suboptimal clinical evidence, the first large, randomized controlled trial (RCT) conducted in critically ill patients showed no effect on 28-day survival as associated with IV administration of 4% albumin, compared with 0.9% sodium chloride, for volume resuscitation. Despite the overall equipoise of the two strategies in the entire study population, the trial suggested, for the first time, a potential benefit of human albumin in the predefined subgroup of patients with severe sepsis. To test such a hypothesis, in 2014, we concluded the first large RCT (ie, the Albumin Italian Outcome Sepsis [ALBIOS] study) comparing an albumin replacement strategy (including albumin and crystalloid administration) vs the use of crystalloids alone, for the first 28 days of treatment in patients with severe sepsis or septic shock. The trial reported no advantages of albumin administration on 28- or 90-day survival. Nonetheless, in a post hoc and not predefined subgroup analysis, patients with septic shock randomized to the albumin group reported a significant 6.3% absolute reduction in 90-day mortality compared with the crystalloid group.