Background & Aims There is conflicting evidence on the effects of thiopurines (azathioprine or mercaptopurine) and anti–tumor necrosis factor (TNF) therapies on rates of surgery among patients with Crohn's disease (CD). We aimed to identify factors that identify patients who are unlikely to respond to medical therapy and will therefore require surgery. Methods We performed a retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry to identify 425 patients diagnosed with CD who received a prescription of a thiopurine and/or an anti-TNF agent from a referral center, from July 1, 1975, through September 13, 2012. We collected data on CD-related abdominal surgery after therapy and disease features when therapy was instituted. Cox proportional regression models were used to associate disease features with outcomes after adjusting for potential confounders. Risk estimates were presented as hazard rate ratios (HRRs) with 95% confidence intervals (CIs). Results Among patients given thiopurines, stricturing disease (adjusted HR, 4.63; 95% CI, 2.00–10.71), ileal location (adjusted HR, 6.20; 95% CI, 1.64–23.42), and ileocolonic location (adjusted HR, 3.71; 95% CI, 1.08–12.74) at the time of prescription were associated significantly with the need for surgery. Prescription of an anti-TNF agent after prescription of a thiopurine reduced the risk for surgery, compared with patients prescribed only a thiopurine (adjusted HR, 0.41; 95% CI, 0.22–0.75). Among patients given anti-TNF agents, stricturing (adjusted HR, 6.17; 95% CI, 2.81–13.54) and penetrating disease (adjusted HR, 3.39; 95% CI, 1.45–7.92) at the time of prescription were associated significantly with surgery. Older age at diagnosis (17–40 y) reduced the risk for abdominal surgery (adjusted HR, 0.41; 95% CI, 0.21–0.80) compared with a younger age group (≤16 y). Surgery before drug prescription reduced the risk for further surgeries among patients who received thiopurines (adjusted HR, 0.33; 95% CI, 0.13–0.68) or anti-TNF agents (adjusted HR, 0.49; 95% CI, 0.25–0.96). Terminal ileal disease location was not associated with a stricturing phenotype. Conclusions Based on a retrospective database analysis, patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery. Better patient outcomes are achieved by treating CD at early inflammation stages; delayed treatment increases rates of treatment failure.