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Objectives A high proportion of Crohn's disease (CD) patients lose response to antitumor necrosis factor (anti-TNF) and therapy needs to be intensified. We aimed to prospectively determine the predictors and frequency of anti-TNF loss of response and therefore the need for dose escalation and de-escalation in CD patients treated with infliximab or adalimumab. Methods All patients were anti-TNF naive while concomitant azathioprine was administered for 6 months. In patients initially responding to anti-TNF and subsequently losing clinical response after the first 14 weeks of therapy, dose escalation was scheduled. During the follow-up period and after 1 year of intensified administration, anti-TNF was de-escalated in patients in remission. Results A total of 161 patients were started on infliximab (n=96) or adalimumab (n=65); however, 29 patients (18.0%) did not respond to therapy and were excluded from further analysis. From the remaining 132 patients (infliximab=77, adalimumab=55), 31 (23.5%) needed a dose escalation for maintenance of remission during a median 28-month follow-up period. Factors associated with loss of response and therefore the need for anti-TNF dose escalation were azathioprine discontinuation earlier than 6 months and smoking. Most patients achieved clinical remission (n=25, 80.6%) without other interventions and among these, 16 patients (64%) were successfully de-escalated to the standard maintenance infliximab or adalimumab dose schedule after 1 year of intensified anti-TNF administration. Conclusion Azathioprine discontinuation earlier than 6 months and smoking in CD patients started on anti-TNF therapy is associated with loss of response and the need for anti-TNF dose escalation.