Background: Intensive care unit (ICU) nurses are at high risk for work-related musculoskeletal disorders (WRMDs). Data on occupational injuries indicate the significance of WRMDs among ICU nurses. Intervention programs have previously been developed to reduce WRMDs, but different intervention methods need to be adopted for different groups of people. This study aimed to evaluate the effectiveness of a multidimensional intervention program to prevent and reduce WRMDs in ICU nurses.Methods: The study was designed as a two-armed cluster controlled trial with an intervention group and a control group. The clusters were independent hospital ICUs, and the participants consisted of registered nurses. By cluster random sampling, 89 nurses from 2 ICUs were assigned to the intervention group, and 101 nurses from 2 other ICUs were assigned to the control group. A multidimensional intervention program based on previous studies was designed. This program combined improving risk perception, health behavior training, and promoting a safe working environment. The multidimensional intervention program was implemented in the intervention group, whereas the routine specialist training was implemented in the control group. Baseline and follow-up (3 and 6 months) data were collected using self-reported online questionnaires. The primary outcome was the report rate of WRMDs in the past 7 days. Secondary outcomes were risk perception, health behavior applied, and perception of a safe working environment. The data were statistically analyzed using SPSS 19.0. Results: A total of 190 nurses provided 3 recorded outcome measurement (intervention group N=89 (94.68%); control group N=101 (94.39%)). After 6 months, the intervention group experienced significant improvement relative to the control group in the report rate of WRMDs in the past 7 days (OR=0.512, p =0.038), risk perception (OR=0.517, p <0.001), health behavior training (OR=0.025, p <0.001), and perception of a safe working environment (OR=1.637, p =0.024). Conclusion: The multidimensional intervention program was superior to routine specialist training in preventing the occurrence of WRMDs in ICU nurses. WRMD training should include multifaceted approaches and pay increased attention to specific aspects of the departmental function.