Understanding the mechanisms of long-standing musculoskeletal pain and adaptations in response to physical rehabilitation is important for developing optimal treatment strategies. The influence of central adaptations of pain perception in response to rehabilitation of musculoskeletal pain remains unclear.To investigate the effect of neck/shoulder resistance training on pressure pain threshold (PPT) of the painful neck/shoulder muscles (upper trapezius) and a non-painful reference muscle of the leg (tibialis anterior) in adults with neck/shoulder pain.Examiner-blinded, parallel-group randomized controlled trial with allocation concealment.ISRCTN60264809 SETTING: Office workplaces in the capital of Denmark.The study contained 198 adults with frequent neck/shoulder pain (174 women and 24 men, mean: age 43 years, duration of pain 186 days during the previous year, computer use 93% of work time) were randomly allocated to 10 weeks of specific resistance training for the neck/shoulder muscles for 2 or 12 minutes per day 5 times a week, or weekly information on general health (control group). Primary outcomes were changes in PPT of the painful neck/shoulder muscles (upper trapezius) and a distant non-painful reference muscle (tibialis anterior) at 10 weeks.PPT of both the trained painful trapezius and the non-trained reference muscle of the leg increased more in the training groups compared with the control group (P < 0.05), providing evidence of central adaptations. The change in PPT of the reference muscle was of similar magnitude to that of the painful muscle. Compared with the control group, the change in PPT of the trapezius and tibialis anterior was 31 (95% CI 3 to 60) kPa and 36 (8 to 65) kPa in the 2 min group, respectively, and 29 (1 to 58) kPa and 36 (7 to 64) kPa in the 12 min group.Blinding of participants is not possible in behavioural interventions.Central adaptations of pain perception occur in response to rehabilitation of musculoskeletal pain. Thus, treating pain in one region of the body reduces sensitivity to pressure in other regions of the body. Clinicians and researchers may use this knowledge to better understand adaptations of pain perception in patients with musculoskeletal pain.