Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNFα prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNFα in a treatment paradigm. PG-PS or HSA (control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNFα or vehicle treatment was begun d1, d7, or d14 post-laparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the % decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as % decrease; gross abdominal score: d1=75% (p=0.003), d7=57% (p=0.18), d14=no change (p=0.99); histologic inflammation: d1=57% (p=0.006), d7=50% (p=0.019), d14=no change (p=0.99)]. This was also reflected in changes in IL-1β, IL-6, TNFα, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNFα beginning d1 or d7 compared to vehicle-treated rats; there was no effect if anti-TNFα was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle-treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNFα therapy is initiated early in the course of Crohn's disease.