Primary care is the most common site for the treatment of depression. Most depressed patients prefer psychotherapy over antidepressant medications, but access barriers are believed to prevent engagement in and completion of treatment. The telephone has been investigated as a treatment delivery medium to overcome access barriers, but little is known about its efficacy compared with face-to-face treatment delivery. To examine whether telephone-administered cognitive behavioral therapy (T-CBT) reduces attrition and is not inferior to face-to-face CBT in treating depression among primary care patients. A randomized controlled trial of 325 Chicago-area primary care patients with major depressive disorder, recruited from November 2007 to December 2010. Eighteen sessions of T-CBT or face-to-face CBT. The primary outcome was attrition (completion vs noncompletion) at posttreatment (week 18). Secondary outcomes included masked interviewer-rated depression with the Hamilton Depression Rating Scale (Ham-D) and self-reported depression with the Patient Health Questionnaire-9 (PHQ-9). Significantly fewer participants discontinued T-CBT (n = 34; 20.9%) compared with face-to-face CBT (n = 53; 32.7%; P = .02). Patients showed significant improvement in depression across both treatments (P < .001). There were no significant treatment differences at posttreatment between T-CBT and face-to-face CBT on the Ham-D (P = .22) or the PHQ-9 (P = .89). The intention-to-treat posttreatment effect size on the Ham-D was d = 0.14 (90% CI, -0.05 to 0.33), and for the PHQ-9 it was d = -0.02 (90% CI, -0.20 to 0.17). Both results were within the inferiority margin of d = 0.41, indicating that T-CBT was not inferior to face-to-face CBT. Although participants remained significantly less depressed at 6-month follow-up relative to baseline (P < .001), participants receiving face-to-face CBT were significantly less depressed than those receiving T-CBT on the Ham-D (difference, 2.91; 95% CI, 1.20-4.63; P < .001) and the PHQ-9 (difference, 2.12; 95% CI, 0.68-3.56; P = .004). Among primary care patients with depression, providing CBT over the telephone compared with face-to-face resulted in lower attrition and close to equivalent improvement in depression at posttreatment. At 6-month follow-up, patients remained less depressed relative to baseline; however, those receiving face-to-face CBT were less depressed than those receiving T-CBT. These results indicate that T-CBT improves adherence compared with face-to-face delivery, but at the cost of some increased risk of poorer maintenance of gains after treatment cessation. clinicaltrials.gov Identifier: NCT00498706.