Background: Current guidelines recommend early enteral nutrition in the critically ill. Nutritional deficiencies in this population may result in unfavorable outcomes. However, enteral nutrition may be complicated with feeding intolerance, aspiration, pneumonia, and interruption of feeding. Objectives: We updated our systematic review and meta-analysis that compared the effect of postpyloric and gastric feeding on risk of pneumonia, duration of mechanical ventilation (MV), Intensive Care Unit (ICU) length of stay (LOS), gastrointestinal (GI) bleeding, aspiration, vomiting, and mortality. Methods: We searched MEDLINE, EMBASE, and clinical registries for data through April 2017 without language or date of publication restrictions. We included randomized controlled trials (RCTS) comparing postpyloric feeding to gastric feeding. Two reviewers independently screened titles and abstracts for eligibility and extracted data in duplicate. Reviewers used the Cochrane Collaboration tool to assess the risk of bias, and the Grading of Recommendations, Assessment, Development, and Evaluation methodology to assess the quality of the evidence. We used trial sequential analysis (TSA) as a sensitivity analysis to adjust for sequential testing. Results: We included 21 RCTs (1573 patients). Postpyloric feeding reduced the risk of nosocomial pneumonia (relative risk [RR] 0.73; 95% confidence interval [CI] 0.57, 0.95; P = 0.02; I2 = 11%; moderate quality), ventilator-associated pneumonia (RR 0.74, 95% CI 0.57, 0.96; P = 0.02; I2 = 10%, moderate quality), and duration of MV (mean difference [MD] - 2.10 days, 95% CI −3.93, −0.28; P = 0.02; I2 = 67%, low quality), compared to gastric feeding. There was no difference in mortality (RR 1.07, 95% CI 0.90, 1.27; P = 0.44; I2 = 0%, moderate quality), ICU LOS (MD - 1.01 days, 95% CI −3.32, 1.3; P = 0.39; I2 = 84%, very low quality), aspiration (RR 0.81, 95% CI 0.4, 1.60, P = 0.54; I2 = 21%, very low quality), vomiting (RR 0.97, 95% CI 0.70, 1.36, P = 0.87; I2 = 33%, very low quality), and GI bleeding (RR 0.88, 95% CI 0.56, 1.38; P = 0.56; I2 = 0%, very low quality). Sensitivity analysis using TSA mirrored those of conventional analyses. Conclusions: Moderate quality evidence showed that postpyloric feeding may reduce the risk of pneumonia. Low-quality evidence yielded that duration of MV is shorter with pyloric compared to gastric feeding, with no significant impact on other outcomes. Although the results are promising further assessment in large clinical trials is warranted.