Objective: Chronic non-specific neck pain (CNP) is a common, often disabling condition which still lacks a reliable therapeutic standard. Empiric evidence suggests that osteopathic interventions might be effective in alleviating CNP symptoms. A randomized controlled clinical trial of efficacy was performed to test this hypothesis. Materials and Methods: 135 CNP sufferers were identified through advertisements, and 41 patients who met all relevant predefined criteria were recruited. All participants received a 12-min session of sham ultrasound once a week for an average of 10 weeks. In addition, a test-dependent osteopathic intervention of 45 min was given to 24 participants every other week. 40 participants could be followed up for 12 weeks after the end of therapy. The main outcome parameter was pain intensity measured on a numeric rating scale (NRS, range: 0–10). Results: There were 2 dropouts in the intervention group and 2 in the control group. Average pain intensity decreased from 4.7 to 2.2 in the osteopathic group (p < 0.0005), and from 4.8 to 4.0 in the control group (p = 0.09). The intergroup difference of longitudinal changes was clearly significant, too (p = 0.02). Further slight but comparable reductions were observed at follow-up (0.3 and 0.4 NRS points, respectively). These changes seem to have a positive impact on quality of life, as assessed by generic and specific instruments such as the MOS SF-36 and the Northwick Park Pain Questionnaire. Conclusions: A series of test-dependent osteopathic interventions may be a promising therapeutic regimen for CNP sufferers. Further studies will have to demonstrate a) whether these findings are reproducible, and b) whether positive long-term outcomes can be achieved.