IMPORTANCE: In the US, access to medication abortion using history-based (no-test) eligibility assessment, including through telehealth and mailing of mifepristone, has grown rapidly. Additional evidence on the effectiveness and safety of these models is needed. OBJECTIVE: To evaluate whether medication abortion with no-test eligibility assessment and mailing of medications is as effective as in-person care with ultrasonography and safe overall. DESIGN, SETTING, AND PARTICIPANTS: Prospective, observational study with noninferiority analysis. Sites included 4 abortion-providing organizations in Colorado, Illinois, Maryland, Minnesota, Virginia, and Washington from May 2021 to March 2023. Eligible patients were seeking medication abortion up to and including 70 days’ gestation, spoke English or Spanish, and were aged 15 years or older. EXPOSURE: Study groups reflected the model of care selected by the patient and clinicians and included: (1) no-test (telehealth) eligibility assessment and mailing of medications (no-test + mail) (n = 228); (2) no-test eligibility assessment and pickup of medications (no-test + pickup) (n = 119); or (3) in-person with ultrasonography (n = 238). MAIN OUTCOMES AND MEASURES: Effectiveness, defined as a complete abortion without the need for repeating the mifepristone and misoprostol regimen or a follow-up procedure, and safety, defined as an abortion-related serious adverse event, including overnight hospital admission, surgery, or blood transfusion. Outcomes were derived from patient surveys and medical records. Primary analysis focused on the comparison of the no-test + mail group with the in-person with ultrasonography group. RESULTS: The mean age of the participants (N = 585) was 27.3 years; most identified as non-Hispanic White (48.6%) or non-Hispanic Black (28.1%). Median (IQR) gestational duration was 45 days (39-53) and comparable between study groups (P = .30). Outcome data were available for 91.8% of participants. Overall effectiveness was 94.4% (95% CI, 90.7%-99.2%) in the no-test + mail group and 93.3% (95% CI, 88.3%-98.2%) in the in-person with ultrasonography group in adjusted models (adjusted risk difference, 1.2 95% CI, −4.1 to 6.4), meeting the prespecified 5% noninferiority margin. Serious adverse events included overnight hospitalization (n = 4), blood transfusion (n = 2), and emergency surgery (n = 1) and were reported by 1.1% (95% CI, 0.4%-2.4%) of participants, with 3 in the no-test + mail group, 3 in the in-person with ultrasonography group, and none in the no-test + pickup group. CONCLUSIONS AND RELEVANCE: This prospective, observational study found that medication abortion obtained following no-test telehealth screening and mailing of medications was associated with similar rates of complete abortion compared with in-person care with ultrasonography and met prespecified criteria for noninferiority, with a low prevalence of adverse events.