Objective This study aims to evaluate the effectiveness of a draft occupational health guideline, aimed at preventing weight gain, on employees' body weight-related outcomes, cardiovascular disease (CVD) risk factors, and quality of life. Methods In a cluster randomized controlled trial including 16 occupational physicians (OP) and 523 employees, guideline-based care was compared to usual care by OP between 2009-2011 in the Netherlands. Guideline-based care consisted of (i) providing advice to employers on how to assess and intervene on the obesogenic work environment, (ii) conducting five face-to-face behavioral change counseling sessions with employees to improve their lifestyles, and (iii) evaluating the outcome and maintaining sections i and ii. Data were collected at baseline and 6, 12, and 18-months follow-up. To evaluate the effects of the intervention, multilevel analyses were performed. Results No significant differences were found between the intervention and control group on waist circumference [beta 1.2 cm, 95% confidence interval (95% CI) -0.6-2.9], body weight (beta 0.3 kg, 95% CI -1.0-1.6), body mass index (beta 0.1 kg/m2, 95% CI -0.3-0.5), systolic blood pressure (beta 1.7 mmHG, 95% CI -2.4-5.8), diastolic blood pressure (beta 0.3 mmHG, 95% CI -1.0-0.6), cholesterol (beta 0 mmol/l, 95% CI -0.2-0.2), or quality of life indicators after 18-months follow-up. Stratified analyses showed an increase in waist circumference among men (beta 2.5 cm, 95% CI 0.5-4.5) and obese intervention participants (beta 2.7 cm, 95% CI 0.6-4.7) compared to control participants. Conclusion The draft occupational health guideline was not more effective than usual care. Therefore, the guideline in its current form cannot be recommended for implementation. This work is licensed under a Creative Commons Attribution 4.0 International License.