IMPORTANCE: Realizing the benefits of cancer screening requires testing of eligible individuals and processes to ensure follow-up of abnormal results. OBJECTIVE: To test interventions to improve timely follow-up of overdue abnormal breast, cervical, colorectal, and lung cancer screening results. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, cluster randomized clinical trial conducted at 44 primary care practices within 3 health networks in the US enrolling patients with at least 1 abnormal cancer screening test result not yet followed up between August 24, 2020, and December 13, 2021. INTERVENTION: Automated algorithms developed using data from electronic health records (EHRs) recommended follow-up actions and times for abnormal screening results. Primary care practices were randomized in a 1:1:1:1 ratio to (1) usual care, (2) EHR reminders, (3) EHR reminders and outreach (a patient letter was sent at week 2 and a phone call at week 4), or (4) EHR reminders, outreach, and navigation (a patient letter was sent at week 2 and a navigator outreach phone call at week 4). Patients, physicians, and practices were unblinded to treatment assignment. MAIN OUTCOMES AND MEASURES: The primary outcome was completion of recommended follow-up within 120 days of study enrollment. The secondary outcomes included completion of recommended follow-up within 240 days of enrollment and completion of recommended follow-up within 120 days and 240 days for specific cancer types and levels of risk. RESULTS: Among 11 980 patients (median age, 60 years IQR, 52-69 years; 64.8% were women; 83.3% were White; and 15.4% were insured through Medicaid) with an abnormal cancer screening test result for colorectal cancer (8245 patients 69%), cervical cancer (2596 patients 22%), breast cancer (1005 patients 8%), or lung cancer (134 patients 1%) and abnormal test results categorized as low risk (6082 patients 51%), medium risk (3712 patients 31%), or high risk (2186 patients 18%), the adjusted proportion who completed recommended follow-up within 120 days was 31.4% in the EHR reminders, outreach, and navigation group (n = 3455), 31.0% in the EHR reminders and outreach group (n = 2569), 22.7% in the EHR reminders group (n = 3254), and 22.9% in the usual care group (n = 2702) (adjusted absolute difference for comparison of EHR reminders, outreach, and navigation group vs usual care, 8.5% 95% CI, 4.8%-12.0%, P < .001). The secondary outcomes showed similar results for completion of recommended follow-up within 240 days and by subgroups for cancer type and level of risk for the abnormal screening result. CONCLUSIONS AND RELEVANCE: A multilevel primary care intervention that included EHR reminders and patient outreach with or without patient navigation improved timely follow-up of overdue abnormal cancer screening test results for breast, cervical, colorectal, and lung cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03979495