Lynch syndrome (LS) is the most prevalent cause of hereditary colorectal cancer (CRC) and confers high risks for several other types of cancer. Universal tumor screening (UTS) of all newly diagnosed patients with CRC can improve LS identification and decrease associated morbidity and mortality among patients and family members. However, for UTS to be effective, patients who screen positive must pursue genetic counseling and confirmatory germline testing (i.e., high patient reach). The purposes of this study were to characterize UTS programs, identify barriers and facilitators to implementation, document whether there have been negative outcomes, and determine institutional and implementation conditions that are associated with high and low patient reach. Using two conceptual frameworks, RE-AIM and Consolidated Framework for Implementation Research, a baseline survey was conducted of 25 representatives from different institutions performing UTS. Descriptive statistics were used to illustrate similarities and differences among programs. A multiple-case study was then conducted by extracting data from surveys and interviews of representatives from 15 different institutions where UTS programs had been operational for over 6 months and where aggregated patient outcome data were available. Qualitative comparative analysis was performed to make systematic cross-case comparisons and identify conditions uniquely associated with high or low patient reach. Data were triangulated to create models explaining how UTS implementation and system-level factors influence patient reach. Few patient concerns or negative outcomes were reported. UTS procedures and patient reach were highly variable. All 5 high-reach (H-R) centers have genetics professionals disclose positive screening results and either do not require a referral from another health care provider or have streamlined the referral process. Although 2 of the 5 mid-reach (M-R) centers also share these conditions, they have a less automated follow-up procedure and report difficulty contacting patients as a barrier. Both of the academic institutions with low patient reach (L-R) did not receive patient information that would allow them to follow-up on positive screening results. The three non-academic L-R institutions reported a high proportion of challenges to facilitators during implementation and did not have genetic professionals disclose positive screening results to patients. Implementing a combination of procedures to streamline UTS protocols and procedures, eliminate barriers to patient follow-through after a positive tumor screen, and incorporate a high level of involvement of genetic professionals in contacting patients and disclosing screening results are expected to lead to improvement in patient reach