Abstract This study examined the effect of 1-monoglycerides and 1,2-diglycerides of butyric-, caproic- and caprylic acid (SILOHealth™ 104L [monoglycerides]) and avilamycin on day 14 and 21 post weaning performance of E. coli (GN-Ent and O157:H7) day 5 challenged piglets fed corn/soy diets that met or exceeded current NRC (2012) recommendations. A total of 96, Choice Genetics CG32, piglets were used in a randomized complete block design with pen as the experimental unit, treatment as the fixed effect, and block as the random effect (4 piglets/pen x 3 treatments x 8 replications). Pigs were blocked by sex and weight and were orally dosed with 5 ml (1x109 CFU/g, strain GN-Ent and O157:H7) E. coli d 5 after weaning (Ec). The treatment were: NC with Ec; T1=NC + 3 kg/MT monoglycerides; T2=NC+ 80 ppm avilamycin. Least significant difference was used to compare means of treatment. Mortalities and pen removals were weighed and recorded. The E. coli infection model was effective in causing E. coli mortality of 25% at d14 post weaning and 33% at d21 post weaning in NC. T1 and T2 reduced mortality versus NC at d14 (25, 3 and 0%, P < 0.05) and d21 (33, 4 and 0%, P < 0.05), increased ADG at d14 (203, 255 and 259 g, P < 0.05) and d21 (456, 511 and 515 g, P < 0.05), decreased FCR at d21 (1.90, 1.85 and 1.83, P < 0.05), and decreased intestinal E. coli, log 10 of CFU/g, versus NC (4.1, 2.2 and 2.1, P < 0.05). Monoglycerides and avilamycin performance, mortality and intestinal E. coli log 10 were not significantly different at P < 0.05. In conclusion, the use of monoglycerides improved ADG, reduced FCR, reduced mortality and reduced intestinal E. coli log 10 at day 14 and 21 post weaning versus NC and monoglycerides were not significant different (P < 0.05) than avilamycin.