Background: There is good evidence that cancer-specific patient outreach improves rates of cervical, breast, and colorectal cancer screening. However, it is unclear how primary care practices should implement integrated outreach for all 3 types of cancer screening. We aimed to understand whether integrated outreach using mailed letters or phone calls were more effective at increasing screening uptake in a primary care organization.Method: We conducted a pragmatic randomized trial comparing outreach by mailed letter or personalized phone call for patients overdue for cervical, breast, or colorectal cancer screening. The study was conducted at 6 clinics within an academic primary care organization in Toronto, Canada. Our primary outcome was an uptake of at least 1 screening test for which the patient was overdue. Our primary analysis was an intention-to-treat, unadjusted comparison of proportions, using a 2 test. We also compared costs per additional patient screened. All analyses were stratified by sex.Results: A total of 3733 females and 1537 males were randomized to receive 1 of the interventions. Among women, 33.0% allocated to receive a reminder letter and 41.2% allocated to receive a reminder phone call received at least 1 screening test for which they were due (absolute difference, 8.1%; 95% CI, 5.1%-11.2%, P < .001). Among men, 24.8% allocated to receive a reminder letter and 28.8% allocated to a reminder phone call received screening for colorectal cancer (absolute difference, 4.1%; 95% CI, ؊0.4% to 8.5%, P ؍ .073). For women and men, the letters cost approximately CaD $5.07 and CaD $7.16, respectively, for each completed screening test compared with CaD $8.71 and CaD $12.00 for the phone calls.Conclusions: Phone calls were more effective than mailed letters at increasing uptake for cervical, breast, and colorectal cancer screening among women. However, phone calls were more expensive than letters. Primary care practices should consider integrating phone call reminders into their practice, possibly as part of a targeted or staged approach to outreach for cancer screening. (J Am Board Fam Med 2018;31:857-868.)