Saturated-fat intake and endotoxemia can impair cognition. However, their acute impact on cognitive performance is unknown. This study assessed the impact of 2 high-fat meals and endotoxemia on attention. In this double-blind, randomized crossover trial, 51 women (n=32 breast cancer survivors, n=19 noncancer controls; mean ± SD age: 53 ± 8 y) completed the Continuous Performance Test (CPT) and had their blood drawn to assess endotoxemia markers LPS binding protein (LBP), soluble CD14 (sCD14), and the LBP to sCD14 ratio 1 h prior to eating either a high-saturated-fat meal or a high-oleic-sunflower-oil meal. Women again completed the CPT 5 h postmeal. At 1 to 4 wk later, women completed the same protocol but consumed the other meal. In adjusted models, women had more difficulty distinguishing target stimuli from distractors after consuming the high-saturated-fat meal than they did after the oleic-sunflower-oil meal (B=4.44, SE=1.88, P=0.02). Women with higher baseline LBP had less consistent response times (B=0.002, SE=0.0008, P=0.04). Those with higher LBP and LBP:sCD14 were less able to sustain their attention throughout the entire CPT, as reflected by their progressively slower (B=0.002, SE=0.0006, P=0.003; and B=2.43, SE=0.090, P=0.008, respectively) and more erratic (B=0.003, SE=0.0008, P<0.0001; and B=3.29, SE=1.17, P=0.006, respectively) response times. Additionally, women with higher baseline LBP or sCD14 were less able to maintain or increase response speeds at higher interstimulus intervals (B=0.002, SE=0.0006, P=0.02; and B=0.006, SE=0.003, P=0.03, respectively), indicating greater difficulty adapting to changing task demands. Significant meal type by LBP and LBP:sCD14 interactions emerged (P<0.05), such that high LBP and LBP:sCD14 erased between-meal cognitive differences, uniformly impairing performance. These results suggest that higher LBP, sCD14, and LBP:sCD14 and saturated-fat intake individually and jointly influence attention. Endotoxemia may override the relative cognitive benefit of healthier oil choices.This trial is registered at clinicaltrials.gov as NCT04247763.