Feed efficiency (FE) is a valuable trait, yet how genetic selection for enhanced FE affects other processes such as response to disease is unknown. Disease from endemic respiratory and enteric pathogens such as Mycoplasma hyopneumoniae (Mh) and Lawsonia intracellularis (LI) are common in swine production. Therefore, the aim of this study was to examine if pigs selected for high versus low FE based on residual feed intake (RFI) respond differently to a dual respiratory and enteric challenge. Pigs selected for low RFI (LRFI, high feed efficiency) pigs are considered more FE compared to their high RFI (HRFI, low feed efficiency) selected counterparts. Using a 2 x 2 factorial design, 25 littermate pairs from the HRFI and 25 littermate pairs from the LRFI line (barrows, 50 ± 7 kg BW) were selected, with one pig from each pair assigned to individual pens in either the challenge or the non-challenge (control) rooms (n = 25 barrows per line/challenge). On days post inoculation (dpi) 0, the challenged pigs were inoculated with LI and Mh (MhLI). Feed intake, body weight, fecal swabs, and serum samples were collected and recorded weekly for 42 days. On dpi -2 and 47, 14 littermate pairs (n=7 barrows per line/challenge) were utilized for initial and final body composition scans using dual X-ray absorptiometry to calculate longitudinal whole body tissue accretion rates for lean, protein, fat, and bone mineral content. Serum antibody levels and fecal shedding of LI were used to confirm infection. Control pigs remained negative by all measures during the 6 week trial and MhLI inoculated pigs were confirmed positive via serological antibody responses by dpi 14 for LI and Mh. There were no interactions between RFI line and challenge status for any overall performance parameter (P > 0.05). The six week MhLI challenge resulted in a 17% reduction in ADG, a 12% reduction in ADFI, and a 7% reduction in G:F versus controls (P < 0.05). In addition, compared to the control pigs, MhLI challenge reduced lean, protein, and lipid accretion rates by 16% (P < 0.05). Genetic selection for high FE resulted in decreased ADFI and increased G:F (P < 0.01), but did not impact ADG or tissue accretion versus low FE pigs. Collectively, these results demonstrate that a dual enteric and respiratory pathogen challenge reduced ADG, ADFI, G:F and tissue accretion in growing pigs. Further, there was no evidence that selection for enhanced FE based on RFI index affects response to disease.