ABSTRACT Objective The present study assessed the differences in nutritional markers (albumin, transferrin, total body fat, and body mass index) and clinical complications (diarrhea, vomiting, and diet interruptions) associated with enteral nutrition. Methods This is an open-label, randomized, two-arm parallel-group controlled clinical trial. Out of 105 patients assessed for eligibility, 35 adult patients were randomly divided into two groups and followed for 28 days. The sample comprised a heterogeneous group of severely ill individuals initially treated in the intensive care units. Neurological conditions (i.e., strokes and brain tumours) were the most common reasons for hospitalization. Patients had one singularity: the clinical need for exclusive enteral nutrition therapy. One group received the diet via gastric tube and the other via a post-pyloric tube. Results The groups presented increases in the calories prescribed and administered, as well as reduced diet discontinuation. Although similar values were observed up to day 21, the post-pyloric group showed increased albumin levels compared to the gastric group on Day 28. Transferrin levels increased over time in both groups. Conclusion There were no differences in the complications recorded between groups, albeit serum albumin significantly increased in the post-pyloric group.