Background: Occupational health guidelines recommend a biopsychosocial approach to manage sickness absence due to musculoskeletal disorders (MSDs), with a primary focus on early intervention through provision of a supportive network. Aims: To investigate the implementation of a guidelines-based intervention (early contact of absentees; addressing psychosocial obstacles; offering temporary modified work; communicating among the players), and to determine whether this is effective for reducing return-to-work times and duration of future absence. Methods: A non-randomized controlled trial was conducted within a UK company. Occupational health nurses at two experimental sites (1435 workers) were trained to deliver the intervention to workers taking absence due to MSDs (low back and upper limb disorders), while usual care was delivered at three control sites (1483 workers). Company-recorded absence data were collected over a 12-month follow-up period. Results: The implementation of the experimental intervention was impeded by unforeseen organizational obstacles at one site (policies, procedures and individual approaches) which had a detrimental effect on uptake and delivery. At the site where the intervention was delivered per protocol, absence was significantly less compared with controls; 6.5 and 10.8 days, respectively. However, the duration of future absence was not significantly different (13.0 and 25.1 days, respectively). Conclusions: An early intervention addressing psychosocial obstacles to recovery can be effective for reducing absence due to MSDs. Successful implementation, where the key players are onside and organizational obstacles are overcome, is difficult to achieve.