BACKGROUND: Microscopic colitis (MC), consisting of collagenous colitis (CC) and lymphocytic colitis (LC), is a notable and often under-recognized cause of diarrheal disease. Standard of care treatment includes the use of anti-diarrheal agents and steroids. However, patients with refractory disease not responding to standard therapy will require escalation of therapy, often to a biologic agent. Data on this population are limited. METHODS: We performed a retrospective, multicenter study of patients diagnosed with MC refractory to steroids requiring treatment initiation with an anti-TNF, anti-integrin, or anti-IL-12/23 from July 2006 to June 2020. Patients with comorbid, rheumatologic, dermatologic, or oncologic disease requiring a biologic agent were excluded. Data regarding disease history and prior and current treatment characteristics were collected. The primary outcome was steroid-free response to biologic therapy defined as cessation of steroids after biologic initiation without further use for a minimum of 90 days. The secondary outcome was duration of steroid-free response, defined as the time to re-initiation of steroids. Patients with CC and LC were compared, and statistical analyses were conducted using the Mann-Whitney U test and Fisher's exact test. RESULTS: Thirty two patients with MC were identified, of whom 19 had CC and 13 had LC. The patients had a median age of 60.5 years, and 93.8% were female. Treatments prior to biologics included budesonide (100%), prednisone (50%), cholestyramine (68.8%), bismuth (37.5%), methotrexate (25.0%), thiopurine (21.9%), and 5-ASA (37.5%). Median (IQR) calprotectin and CRP within 3 months of biologic treatment initiation were 61.5 mcg/g (15.6–109.6) and 1.6 mg/L (1.0–2.6), respectively. The median time from diagnosis of MC to biologic initiation was 1,095 days overall, with 1,642 days for those with CC and 851 days for those with LC (P = 0.03). No additional significant differences in clinical characteristics or prior treatments were found among those with CC vs LC. All patients were started on a biologic: vedolizumab (n = 16), adalimumab (n = 10), infliximab (n = 6). Overall, steroid-free response was observed in 71.2% of patients. Steroid-free response was observed in 75.0% of patients on vedolizumab (n = 16), 70.0% of patients on adalimumab (n = 10), and 66.7% of patients on infliximab (n = 6). The overall duration of steroid-free response had a median days (IQR) of 391 (120–741): vedolizumab 400.5 (260–533), adalimumab 120 (82–491), and infliximab 1,475 (759.5–1,625). There was no significant difference in steroid free response between patients with LC vs CC (61.5% vs 79.0%, P = 0.25), though steroid-free response with vedolizumab was observed in 88.9% of patients with CC and 57.1% of patients with LC (P = 0.26). Patients with CC experienced a shorter median days (IQR) duration of steroid-free response compared to patients with LC: 131 (81–508) vs 524.5 (389–1,101), P = 0.07). Additionally, the duration of steroid-free response with adalimumab was median (IQR) 120 days (82–120) for patients with CC vs 616 days (491–741) for patients with LC (P = 0.05). CONCLUSION: Anti-TNFs and anti-integrins may be treatment options for patients with MC not responding to standard therapy.