Abstract Background Therapeutic drug monitoring (TDM) of infliximab (IFX) improves patient outcomes and is cost-effective. The short turnaround time of point-of-care testing (POCT) allows ad hoc dose adjustment. We aimed to determine the feasibility and pilot effectiveness of an ultra-proactive TDM algorithm including POCT of IFX in patients with inflammatory bowel disease (IBD). Methods All IBD patients with maintenance IFX treatment at our referral IBD clinic were prospectively included between June and August 2018. An ultra-proactive IFX TDM algorithm was applied as follows. All patients had an ELISA trough level (TL) measurement at baseline, of which the result determined the follow-up pathway: (A) TL between 3–7 μg/ml: continuation at same dose and interval; (B) TL >7 μg/ml: interval prolongation allowed; (C) TL <3 μg/ml: interval shortening with minimum 2 weeks, with the next IFX TL measured using a POCT. (i) If the POCT showed an IFX TL <3 μg/ml, dose was optimised ad hoc using a linear dosing formula (Dosen = (TLtarget * Dosen−1) / TLmeasured), followed by a new POCT test at next visit with the same interval. (ii) If the POCT showed an IFX TL ≥3 μg/ml, no additional dose was given and routine TL testing with ELISA was retaken at next visit. Physician’s global assessment, C-reactive protein (CRP), haemoglobin and albumin levels were sequentially evaluated according to standard of care. Results In total, 115 patients were included (Crohn’s disease/ulcerative colitis/IBDU n = 80/34/1; median CRP 1.2 mg/l (IQR 0.6–3.8); median TL 4.6 μg/ml (IQR 2.6–7.4)). A median of 3 infusions (IQR 3–4) during follow-up led to a total number of 371 TL measurements. There was a significant drop of low TL (<3 μg/ml) over time (38/115 at baseline vs. 22/256 during follow-up; p = 0.0001). The need for POCT reduced from an initial 28% to 8.7% (p = 0.0001). Additional dosing based on POCT measurement was needed in 7/43 (16.3%) cases. Patients needing ad hoc dose adjustment after interval shortening had significant lower TL at the previous measurement than those who did not (median (IQR) TL 0.9 μg/ml (0.7–1.8) vs. 2.3 μg/ml (1.5–2.6); p = 0.036). An IFX TL cut-off of 1 µg/ml predicted an ad hoc extra dose after interval shortening with an NPV of 96% (90% sens, 75% spec). In patients with elevated CRP at baseline (n = 26), ultra-proactive TDM resulted in a significant reduction of CRP over time, with a median (IQR) of 7.8 (6.5–18.3) mg/l at baseline compared with 6.3 (4–9.9) mg/l during follow-up (p = 0.025). Conclusions Ultra-proactive TDM based on a strict algorithm including POCT and ad hoc dose adjustment is feasible and significantly lowers CRP levels in IBD patients treated with maintenance IFX. Less than 10% of patients need POCT over time.