The successful transfer of clinical practice guidelines (CPGs) into patient care depends on the appropriateness of the implementation method. This study strived for a better understanding of which intervention strategy is effective in implementing the CPG on Parkinson's disease (CPG-PD). In a cluster randomized controlled trial, we compared the impact of two different implementation strategies of the CPG-PD on health outcomes of PD patients. The primary outcome of health-related quality of life was measured by PDQ-39. The neurologists of the intervention group (IG) versus a control group (CG) received the CPG-PD with special instructions, a 4-h training and were offered personal feedback. Patients were followed over three assessment times: baseline, post-test (6 months) and follow-up (9 months). Lack of time and remuneration resulted in low study participation (32 out of 619 contacted neurologists). Multilevel modelling revealed that primary (PDQ-39) and secondary efficacy variables (EQ-5D, CGI, HADS-D, ZUF-8) of 386 patients were not affected significantly by the intervention and failed to show any significant difference between the two groups. The EQ-5D VAS scale (p = 0.0288) and the CGI-P severity scale (p = 0.0072) showed a significant worsening over time. A significant decrease of hours of dyskinesias in the IG (p = 0.007) was observed, whereas Parkinson symptoms did not change significantly between the groups. Lacking awareness of the CPG-PD seems to be no longer a barrier for its use, but it is still a major challenge to find effective implementation methods to optimise clinical outcome. Further studies are needed for a more comprehensive understanding of successful implementation strategies.