Purpose <p>Leukocyte count is widely available and included in Intensive Care Unit prognostic systems. We hypothesised that the relationship between leukocytosis and mortality risk might differ in critically ill patients admitted <i>with infection</i>, where leukocytosis may be an adaptive response.</p> Methods <p>We performed a registry-based study using the Australian and New Zealand Intensive Care Society Adult Patient Database between 2010 and 2023, across 212 Intensive Care Units. Using descriptive statistics and mixed-effects multivariable logistic regression, we evaluated the association between early peak leukocyte count and mortality, according to whether infection was the primary diagnosis.</p> Results <p>We examined 2,016,578 patients, of whom 1,742,195 had non-infective illnesses (86.4%). In this group, there were 115,613 (6.6%) deaths, and a progressive increase in the adjusted odds of mortality as leukocyte counts increased above 8 × 10⁹/L, peaking at 40 × 10⁹/L (adjusted odds ratio 2.40 (99% CI 2.16–2.66)). This was equivalent to a rise in risk-adjusted mortality from 5.4% (99% CI 5.1–5.6) for leukocyte counts of 8–12 × 10⁹/L, to 9.4% (99% CI 8.6–10.1) for leukocyte counts at 40 × 10⁹/L. Amongst 274,383 patients with infection, there were 37,350 (13.6%) deaths. Leukocytosis had no effect on the odds of mortality. This group had a risk-adjusted mortality of 12.8% (99% CI 12.2–13.3) for leukocyte counts of 8–12 × 10⁹/L and 13.0% (99% CI 11.8–14.1) for leukocyte counts at 40 × 10⁹/L. Lower leukocyte counts, even within the normal range, were associated with mortality in both groups.</p> Conclusion <p>The presence of infection determines the prognostic significance of leukocytosis in the critically ill.</p>