Background To examine the effect of smoking on need for surgery in patients with moderate to severe Crohn’s disease (CD) receiving biologic therapy. Methods Retrospective study of adult patients with CD at a University Medical Center over a 20-year period. Results A total of 251 patients were included (mean age 35.9 ± 15.0; 70.1% males; current, former, and non-smokers: 44.2%,11.6%, and 43.8%, respectively). Mean duration on biologics was 5.0 ± 3.1 years (>2/3 received anti-TNFs, followed by ustekinumab in 25.9%) and a third of patients (29.5%) received > one biologic. Disease-related surgeries (abdominal, perianal or both) occurred in 97 patients (38.6%): 57 before, and 41 after starting biologics. There was no significant difference in surgeries between ever-smokers (current or previous) vs. non-smokers in the overall study group. On logistic regression, the odds of having any CD surgery were higher in patients with longer disease duration (OR = 1.05, 95% CI = 1.01, 1.09) and in those receiving > one biologic (OR = 2.31, 95% CI = 1.16, 4.59). However, among patients who had surgery prior to biologic therapy, smokers were more likely to have perianal surgery compared to non-smokers (OR = 10.6, 95% CI = 2.0, 57.4; p=0.006). Conclusion In biologic-naive CD patients requiring surgery, smoking is an independent predictor of perianal surgery. Smoking, however, is not an independent risk factor for surgery in this cohort after starting biologics. The risk of surgery in those patients is primarily associated with disease duration and the use of more than one biologic.