Chronic back pain (CBP) is a major global health problem, while its treatment is hampered by a lack of efficacy and restricted safety profile of common frontline therapies. The present trial aims to determine whether a 3-week open-label placebo treatment reduces pain intensity and subjective and objective functional disability in patients with CBP. This randomized controlled trial, following a pretest-posttest design, enrolled 127 patients with CBP (pain duration >12 weeks) from the Back Pain Center, Neurology, University Hospital Essen, Germany. Patients randomized to the open-label placebo group received a 3-week open-label placebo treatment. Patients in the treatment as usual (TAU) group received no intervention. Both groups continued TAU. Primary outcome was the change in pain intensity. Secondary outcomes included patient-reported functional disability and objective measures of spine mobility and depression, anxiety, and stress. One hundred twenty two patients with CBP were randomized to the open-label placebo group (N = 63) or TAU group (N = 59). Open-label placebo application led to a larger reduction of pain intensity (-0.62 ± 0.23 vs 0.11 ± 0.17, all M ± SE, P = 0.001, d = -0.44) as well as patient-reported functional disability (3.21 ± 1.59 vs 0.65 ± 1.15, P = 0.020, d = -0.45) and depression scores (-1.07 ± 0.55 vs 0.37 ± 0.39, P = 0.010, d = -0.50) compared with TAU only. Open-label placebo treatment did not affect objective mobility parameters, anxiety and stress. Our study demonstrates that a 3-week open-label placebo treatment is safe, well tolerated and reduces pain, disability, and depressive symptoms in CBP. Trial registration: German Clinical Trials Register, DRKS00012712.