RATIONALE AND OBJECTIVE: In budget-constrained health systems, decision makers need to consider both the costs and effects of introducing and actively implementing clinical guidance. We aim to demonstrate how, as an alternative to conventional methods, a total net benefit approach to economic evaluation can be used to inform decision making about guidelines and specific implementation strategies, like education or financial incentives. METHODS: Aside from providing more detail on the decision framework, we describe how to collect and analyse the relevant data for calculating the total net benefit of guideline use and the value of implementation. We illustrate the process of decision analysis for a stylized example on improving diabetes care in the UK. For the analysis, economic evidence on intensified glycemic control and that on audit and feedback to promote control is combined with information on diabetes practice. RESULTS: Our illustration demonstrates that the total net benefit of guideline use and the value of implementation can vary substantially, depending on the clinical intervention chosen, the health system being studied and the specific implementation strategies. This also holds for the threshold value for cost-effectiveness, the duration of guideline usage or validity, the size of the patient population served, and the trends and ceiling rates in the implementation of clinical guidance. CONCLUSIONS: In comparison with conventional methods for health economic evaluation, a total net benefit approach allows for the explicit consideration of the current (or future) use of guidelines or guideline recommendations, the cost of implementation and the scope of clinical practice. Decisions made on the basis of the total net benefit of all plausible combinations of clinical guidance and implementation strategies provide optimal patient care and an efficient use of resources.