Abstract This study evaluated a Lactobacillus fermentation postbiotic (LFP) in nursery pigs challenged with F18 ETEC. A total of 119 three-week-old barrows and gilts were used in this study. Pigs were acclimated for a period of 7 d upon arrival at the facility before inoculation. Pigs were stocked in mixed-sex pens of 6 pigs in each pen. Four rooms were used and each room had 5 pens. One room of pigs was not challenged with F18 ETEC (NCH). Ninety pigs in the other 3 rooms were intraorally challenged for three consecutive days with F18 ETEC isolate at a concentration of ~1x109 cfu/ml (CH) Pigs in the non-challenge groups were housed in separate airspaces than those receiving ETEC inoculum to avoid contamination. All pigs, regardless of health challenge, were fed a standard two-phase dietary nursery program. Five dietary treatments were evaluated: T1) negative dietary control without feed additives (Carabox, zinc oxide, and added copper), T2) 750 ppm LFP, T3) 1,500 ppm LFP, T4) 2,250 ppm LFP, and T5) positive control (PC) with feed additives. Feces were collected at 0 and 4 d post inoculation (dpi) to evaluate fecal shedding by real time polymerase chain reaction (rtPCR). Pig body weights were collected at -7, 0, 7, 14, 21, and 42 dpi to calculate performance. Feed intake was measured at the completion of the two dietary phases at 7 and 42 dpi for calculation of average daily feed intake (ADFI) and gain to feed ratio (G:F). All pigs were negative for F18 ETEC on 0 dpi and the non-challenge pigs remained negative by 4 dpi. At 4 dpi, the pigs fed 1,500 and 2,500 ppm LFP had significantly less Cts than pigs fed the positive control (rtPCR < 0.819, P = 0.03). Pigs fed the negative control had significantly greater fecal bacterial load than those fed the positive control averaged across challenge treatments and dpi (Ct ratio = 0.84, P = 0.03). Total E. coli and overall bacterial load were increased at 0 dpi compared with 4 dpi (Ct ratio= 0.90, P < 0.02). Pigs fed the positive control grew significantly faster than those fed the other diets during the acclimation phase (P < 0.01). Pigs in T5 were heavier than those on T1 at 14 and 21 dpi P < 0.02; table 1). End weights, average daily gain (ADG), and ADFI were similar between T1 and T2-4 across dietary phases (P = 0.13) with a tendency for the pigs feed 1,500 ppm to be heavier at d 21 (linear effect, P = 0.15) Pigs fed the positive control were heavier and grew faster at the end of each phase compared with pigs fed the other diets. The F18 challenge was effective in decreasing pig performance. Preliminary evidence suggests lactobacillus fermentation postbiotic may improve nursery performance in the face of an F18 challenge, but further investigation is necessary.