Background: Blended behavior change interventions combine therapeutic guidance with online care. This new way of delivering health care is supposed to stimulate patients with chronic somatic disorders in taking an active role in their disease management. However, knowledge about the effectiveness of blended behavior change interventions and how they should be composed is scattered. Objective: This comprehensive systematic review aimed to provide an overview of characteristics and effectiveness of blended behavior change interventions for patients with chronic somatic disorders. Methods: We searched for randomized controlled trials published from 2000 to April 2017 in PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials. Risk of bias was assessed using the Cochrane Collaboration tool. Study characteristics, intervention characteristics, and outcome data were extracted. Studies were sorted based on their comparison group. A best-evidence synthesis was conducted to summarize the effectiveness. Results: A total of 25 out of the 29 included studies were of high quality. Most studies (n=21; 72%) compared a blended intervention with no intervention. The majority of interventions focused on changing pain behavior (n=17; 59%), and the other interventions focused on lifestyle change (n=12; 41%). In addition, 26 studies (90%) focused on one type of behavior, whereas 3 studies (10%) focused on multiple behaviors. A total of 23 studies (79%) mentioned a theory as basis for the intervention. The therapeutic guidance in most studies (n=18; 62%) was non face-to-face by using email, phone, or videoconferencing, and in the other studies (partly), it was face-to-face (n=11; 38%). In 26 studies (90%), the online care was provided via a website, and in 3 studies (10%) via an app. In 22 studies (76%), the therapeutic guidance and online care were integrated instead of two separate aspects. A total of 26 outcome measures were included in the evidence synthesis comparing blended interventions with no intervention: For the coping strategy catastrophizing, we found strong evidence for a significant effect. In addition, 1 outcome measure was included in the evidence synthesis comparing blended interventions with face-to-face interventions, but no evidence for a significant effect was found. A total of 6 outcome measures were included in the evidence synthesis comparing blended interventions with online interventions, but no evidence for a significant effect was found. Conclusions: Blended behavior change interventions for patients with chronic somatic disorders show variety in the type of therapeutic guidance, the type of online care, and how these two delivery modes are integrated. The evidence of the effectiveness of blended interventions is inconsistent and nonsignificant for most outcome measures. Future research should focus on which type of blended intervention works for whom.