A high-fat diet has been associated with increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included higher quantities of fruits, vegetables, and fiber than a typical SAD). We collected data on quality of life, markers of inflammation, and fecal markers of intestinal dysbiosis in patients with UC.We analyzed data from a parallel-group, cross-over study of 17 patients with UC in remission or mild disease (with a flare within the last 18 months), from February 25, 2015 through September 11, 2018. Participants were randomly assigned to 2 groups and received a LFD (10% of calories from fat) or an iSAD (35%-40% of calories from fat) for the first 4-week period, followed by a 2-week wash-out period, and then switched to the other diet for 4 weeks. All diets were catered and delivered to patients' homes, and each participant served as her or his own control. Serum and stool samples were collected at baseline and week 4 of each diet and analyzed for markers of inflammation. We performed 16s rRNA sequencing and untargeted and targeted metabolomic analyses on stool samples. The primary outcome was quality of life, which was measured by the short inflammatory bowel disease (IBD) questionnaire at baseline and week 4 of the diets. Secondary outcomes included changes in short-form 36 health survey, partial Mayo score, markers of inflammation, microbiome and metabolome analysis, and adherence to the diet.Participants' baseline diets were unhealthier than either study diet. All patients remained in remission throughout the study period. Compared to baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and short-form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD P=.02; baseline vs LFD P=.001). Serum amyloid A significantly decreased from 7.99 mg/L at baseline to 4.50 mg/L after LFD (P=.02) but did not decrease significantly compared to iSAD (7.20 mg/L; iSAD vs LFD, P=.07). Serum level of C-reactive protein decreased numerically from 3.23 mg/L at baseline to 2.51 mg/L after LFD (P=.07). Relative abundance of Actinobacteria in fecal samples decreased from 13.69% at baseline to 7.82% after LFD (P=.017), whereas relative abundance of Bacteroidetes increased from 14.6% at baseline to 24.02% on LFD (P=.015). Relative abundance of Faecalibacterium prausnitzii was higher after 4 weeks on the LFD (7.20%) compared with iSAD (5.37%; P=.04). Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD P=.05; iSAD vs LFD, P=.09). Fecal level of tryptophan decreased from a relative abundance of 1.33 at baseline to 1.08 on the iSAD (P=.43) but increased to a relative abundance of 2.27 on the LFD (baseline vs LFD P=.04; iSAD vs LFD P=.08); fecal levels of lauric acid decreased after LFD (baseline, 203.4; iSAD, 381.4; LFD, 29.91; baseline vs LFD P=.04; iSAD vs LFD P=.02).In a cross-over study of patients with UC in remission, we found that a catered, LFD or iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples. Dietary interventions might therefore benefit patients with UC in remission. ClinicalTrials.gov no: NCT04147598.