Abstract Background Biologic therapies are effective in inducing sustained clinical and endoscopic remission in inflammatory bowel diseases. While side effects are infrequent, prior studies have inconsistently suggested that tumour necrosis factor α (anti-TNF) therapy may be associated with weight gain. We performed this prospective study to compare weight gain across different biologic therapy classes with distinct mechanisms of action. Methods This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab or ustekinumab. Weight measurements were performed at weeks 0, 14, 30 and 54. Disease activity at these time points was assessed using the Harvey Bradshaw Index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC. Remission was defined as HBI <4 or SCCAI 2. Changes in weight between baseline and each of the follow-up visits were modelled as a continuous variable and multivariate regression assessed the independent effect of therapeutic class on this outcome. Results Our study enrolled 314 patients (197 CD, 117 UC) initiating biologic therapy with 120 patients starting anti-TNF (38%), 140 patients started vedolizumab (45%) and 54 patients on ustekinumab (17%). All patients provided their weight and height at baseline; 261, 184 and 131 patients provided data on weight at week 14, week 30 and week 54, respectively. The mean baseline body weight was similar among all therapeutic classes. Patients initiating UST were more likely to have Crohn’s disease (CD), have perianal involvement and have prior biologic exposure. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg ( ± 3.8kg, p = 0.004) and continued to increase compared with baseline with 0.96 kg ( ± 3.9kg, p < 0.001) and 1.29 kg ( ± 4.2kg, p < 0.001) at week 30 and 54, respectively (Figure 1). On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain was seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at week 14, week 30, week 54, respectively) (Figure 2). Weight gain at week 14 was significantly higher in those with CD (+1.25 kg, 95% CI 0.19–2.30, p = 0.021) and being on steroids at baseline (+1.07kg, 95% CI 0.03–2.10, p = 0.043). Early weight gain predicted continued weight gain at week 30 (+0.83kg, 95% CI 0.63–1.03, p < 0.001) and week 54 (+0.48, 95% CI 0.21–0.74, p = 0.001). Neither clinical response to therapy nor disease activity parameters showed any statistical association with weight gain. Conclusion There was no difference in weight gain between the different biologic therapeutic classes.