PurposeWe assessed fecal immunochemical test (FIT) uptake following a mailed FIT intervention among 45–49-year-olds newly eligible for colorectal cancer (CRC) screening based on 2021 United States Preventive Services Task Force screening recommendations. We also tested the effect of an enhanced versus plain mailing envelope on FIT uptake.MethodsIn February 2022 we mailed FITs to eligible 45–49-year-olds at one Federally Qualified Health Center (FQHC) clinic. We determined the proportion who completed FITs within 60 days. We also conducted a nested randomized trial comparing uptake using an enhanced envelope (padded with tracking label and colored messaging sticker) versus plain envelope. Finally, we determined the change in CRC screening by any modality (e.g., FIT, colonoscopy) among all clinic patients in this age group (i.e., clinic-level screening) between baseline and 6 months post-intervention.ResultsWe mailed FITs to 316 patients. Sample characteristics: 57% female, 58% non-Hispanic Black, and 50% commercially insured. Overall, 54/316 (17.1%) returned a FIT within 60 days, including 34/158 (21.5%) patients in the enhanced envelope arm versus 20/158 (12.7%) in the plain envelope arm (difference 8.9 percentage points, 95% CI: 0.6–17.2). Clinic-level screening among all 45–49-year-olds increased 16.6 percentage points (95% CI: 10.9–22.3), from 26.7% at baseline to 43.3% at 6 months.ConclusionCRC screening appeared to increase following a mailed FIT intervention among diverse FQHC patients aged 45–49. Larger studies are needed to assess acceptability and completion of CRC screening in this younger population. Visually appealing mailers may improve uptake when implementing mailed interventions.Trial registrationThe trial was registered on May 28, 2020 at ClinicalTrials.gov (identifier NCT04406714).