Objectives Preventable adverse drug events (ADEs) are closely related to administration processes of parenteral medication. The Dutch Patient Safety Program provided a protocol for administering parenteral medication to reduce the amount of ADEs. The execution of the protocol was evaluated and a cost estimation was performed to provide insight in the associated costs of protocol compliance. Methods A longitudinal evaluation study was performed in secondary care. A total of 2154 observations of the administration process of parenteral medication were carried out within 10 measurements in 19 hospitals between November 2011 and December 2012. The total time needed for the process was measured in a sample of five hospitals. Multilevel linear and logistic regression analyses were used to analyse the trend over time of the implementation and to assess the association between hospital and administration characteristics, and compliance of the protocol. A cost estimation provided insight into the costs of performing a complete administration process and the costs at department level for 1 year. Results The complete protocol was performed in 19% of the observations. The proceeding ‘check by a second nurse’ was least performed. Large differences were found between individual hospitals in performing the administration protocol. The compliance of the protocol was negatively influenced in case of disturbance of the administrator. The overall trend over time of completion of the protocol fluctuated during the study period. On average, 3 min 26 s were needed to perform the complete protocol, which costs €2.42. Extrapolating the costs to department level, including cost for clinical lessons, the difference in costs in performing the complete protocol and an incomplete protocol was €7.891 for 1 year. Conclusions The protocol for administering parenteral medication is still not implemented completely, therefore an investment in time and Euros is needed.