Purpose Physicians not infrequently encounter very sick sepsis patients with normal serum lactate. This phenomenon of lactate discordance, where the serum lactate does not match illness severity, is poorly understood. Methods Using three intensive care unit (ICU) datasets from the U.S. and Spain, we identified adult sepsis patients in the highest quartile of severity of illness scores with at least 1 serum lactate measurement available within 24 hours of ICU admission. Separate logistic regression, random forests and partial least square models were built for each data set to identify characteristics differentiating patients with normal versus high serum lactate and cross-validated in the other datasets. Results Of the 4,861 sickest patients identified, approx. 47% had normal lactate levels. Patients with normal serum lactate levels had lower 28-day mortality rates than those with high lactate levels (17% versus 40%) despite comparable physiologic phenotype. While performance varied between datasets, logistic regression consistently performed best (Area under the receiver operator curve 87-99%, accuracy 79-97%).The variables most strongly associated with normal serum lactate were serum chloride, bicarbonate and blood urea nitrogen, while liver disease, coagulopathy and serum sodium were associated with high serum lactate. Conclusion These analyses provide initial insights on patient characteristics associated with normal serum lactate levels among patients with high illness severity. Additional studies should be performed to confirm these findings and establish the underlying pathophysiological mechanisms. The next step is to disentangle which associations represents an etiology, consequence or an epiphenomenon of high versus normal serum lactate among the sickest patients in the ICU.