Apoptosis inhibitor of macrophage (AIM)/CD5L may be a valuable tool to predict mortality among critically ill patients with sepsis, according to this study. On the day they were admitted to the intensive care unit (ICU), 150 adult patients with sepsis were evaluated for serum AIM levels; these data were compared to survival status and organ function. Outcomes in 60 adult sepsis patients from a different medical center (validation cohort) were also evaluated, as well as 51 pediatric sepsis patients. Adults with sepsis had significantly higher serum AIM levels at ICU admission compared to ICU and healthy control patients. Increased serum AIM levels were significantly correlated with higher Sequential (sepsis-related) Organ Failure Assessment (SOFA) scores. Serum AIM levels on day of ICU admission had a greater association with 28-day mortality as measured by the area under the receiver operating characteristic curve (AUC) (0.86) compared to the AUC for SOFA (0.77), procalcitonin (0.73), lactate (0.67), IL-27 (0.65), and C-reactive protein (0.55). Sepsis patients with AIM levels >543.66 ng/mL at ICU admission had significantly higher 28-day mortality than patients whose AIM admission levels were ≤543.66 ng/mL. The validation cohort confirmed the association between AIM levels and 28-day mortality. In the pediatric cohort, the AUC for the relationship between AIM level and 28-day mortality was 0.82.