PurposeSupervisors play a crucial role in sustainable employment of employees with a work disability. The ‘Mentorwijs’ (literal translation: Mentorwise) training was developed to train supervisors in knowledge, attitudes and skills needed to guide these employees. This study evaluated the effect of ‘Mentorwijs’ on employees’ employment and supervisors’ behavioral outcomes.MethodsRegister- and questionnaire data were obtained from 73 employees and 1,526 matched controls to measure employment (≥ 1/month, ≥ 12 h/week and ≥ 3 consecutive months (≥ 1 h/month)) during a 12-month follow-up period. Questionnaire data were obtained from 127 supervisors who followed the ‘Mentorwijs’ training, to assess their knowledge, self-efficacy, intention to adopt and applied behaviors.ResultsEmployment for ≥ 1 h/month did not significantly improve after 3 (β = 0.05; CI=-0.07-0.16), 6 (β = 0.07; CI=-0.04-0.18), 9 (β = 0.08; CI=-0.02-0.18) and 12 (β = 0.01; CI=-0.08-0.10) months among employees whose supervisors followed ‘Mentorwijs’ compared to those who did not. Significant effects were found after 8 months (β = 0.11; CI = 0.01–0.21). Comparable effects were found for employment ≥ 12 hour/week and ≥ 3 consecutive months (≥ 1 hour/month). Supervisors’ knowledge and self-efficacy significantly improved as a result of ‘Mentorwijs’, but no effects were found for intention to adopt and applied behaviors.Conclusions‘Mentorwijs’ is a promising training to improve the guidance of employees with a work disability. Further research is needed to examine how long-term effects of ‘Mentorwijs’ on employment can be sustained.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10926-023-10118-2.