The present study examined the relationship between therapeutic alliance and both depression and health outcomes in a randomized clinical trial of 2 telephone-administered treatments with 97 clients with multiple sclerosis (MS). The 16-week, manualized treatments compared were telephone-administered cognitive-behavioral therapy (T-CBT) and telephone-administered supportive emotion focused therapy (T-SEFT), an experiential treatment. Alliance scores were significantly higher in T-CBT compared with T-SEFT, and treatment moderated the relationship between alliance and outcome on some of the measures. Specifically, alliance predicted subsequent improvements in depression within the T-CBT condition, but not in T-SEFT, controlling for early symptom change. The authors found a similar trend for alliance and MS-related disability in T-CBT only. This is one of the first studies to examine the role of alliance in outcome for the emerging modality of telephone therapy and one of the few to relate alliance to health outcomes. The findings suggest that the therapist-client relationship is important to improvement in telephone therapy and that the role of alliance in outcome may vary by treatment approach.