Abstract Objective Patients with chronic low back pain (CLBP) and comorbid depression or anxiety disorders are highly prevalent. Negative affect (NA) refers to a combination of negative thoughts, emotions, and behaviors. CLBP patients with high NA have greater pain, worse treatment outcomes, and greater prescription opioid misuse. We present the protocol for SYNNAPTIC– SYNergizing Negative Affect & Pain Treatment In Chronic pain. Design A randomized comparative effectiveness study of antidepressants, fear avoidance rehabilitation, or their combination in 300 CLBP patients with high NA. SYNNAPTIC includes an adaptive design in the antidepressant or rehabilitation only arms of rerandomization after four months for non-responders. Setting A multisite trial conducted in routine pain clinical treatment settings—pain clinics and physical and occupational therapy treatment centers Methods Inclusion criteria include CLBP with elevated depression and anxiety symptoms. Antidepressant and rehabilitation treatments follow validated and effective protocols for musculoskeletal pain in patients with high NA. Power and sample size are based on superior outcomes of combination therapy of these same treatments in a 71-subject 4-arm pilot randomized controlled trial. Conclusions SYNNAPTIC addresses the lack of evidence-based protocols for the treatment of the vulnerable subgroup of patients with CLBP and high NA. We hypothesize that combination therapy of antidepressants + fear avoidance rehabilitation will be more effective than each treatment alone.