Objectives: The aim of this study is to present the adaptation and implementation of the recommendations of the National Institute for Safety and Health at Work (Instituto Nacional de Seguridad y Salud en el Trabajo – INSHT) in the authors’ hospital to achieve a safer handling of hazardous drugs. Material and Methods: In 2016, INSHT published the first document on hazardous drugs in Spain. In the authors’ center, a project was developed to implement the recommendations presented in that document in 2 phases: 1) analysis: to identify drugs and processes susceptible to not being handled as hazardous, and to search for safer alternatives and preventive measures; and 2) development: to ensure information, training, the adaptation of standardized work procedures, the minimization of risks associated with handling, safety devices, personal protective equipment (PPE), as well as health monitoring. Results: The authors detected 80 commercial presentations manipulated without adhering to safety conditions, mainly oral (74%) from lists 1 (7.5%), 2 (37.5%) and 3 (55%) of the National Institute for Occupational Safety and Health. The following measures were envisaged to reduce the risk: introducing new presentations (4 lower doses, 1 liquid dose) and centralizing new preparations in the pharmacy service (11 oral formulas, 6 parenteral drugs). Management, spillage and exposure procedures were adapted. Safety measures were included in the prescription and administration applications, and there were some indications of risks in the storage. Overall, 48 referents and 690 nurses were trained. Each unit was provided with PPE and safety devices (e.g., closed systems, RX CRUSH^®). The steps prior to the administration were moved to the patient’s bedside to align patient and professional safety. During the first 6 months after the implementation, 22 cases of pregnancy (64% among the nursing staff), 4 cases of lactation, and 1 case of conceiving problems were reported. In the cases of oxytocin and the repackaging of list 3, risk management was applied. Conclusions: The multidisciplinary approach has allowed to achieve a global and safer control of hazardous drugs with a minimal impact on the center. It is important to continuously evaluate the effects of these measures, and to take into account the data of this analysis and any possible new evidence. Int J Occup Med Environ Health. 2020;33(5):621–34