OBJECTIVES In recent years, spending on prescription drugs contributes substantially to the continuous growth in health expenditure which is influenced by both a rise in the use of existing drugs and by the adoption of new and expensive drugs. However, their effectiveness outside of clinical trial settings is often uncertain at the time they gain market approval. This uncertainty may reflect a lack of real-world outcomes data, as opposed to clinical trials data, for a typical patient population. A risk-sharing agreement is a contract between a drug manufacturer and a healthcare provider/payer to help manage uncertainties regarding the cost and effectiveness of those drugs and serves the interests of both. Guidelines can be very useful to identify these uncertainties and select the pharmaceuticals which are most eligible for such an agreement to be implemented. To our knowledge, there are no such published guidelines in Spain. METHODS This guidance was designed with the main aim of identifying uncertainties, helping select the pharmaceuticals most eligible, and defining best type of risk sharing agreement (RSA) / pay per results scheme (PRS) to be implemented between the Catalan Heath System (CatSalut) and health care providers/pharmaceutical companies in Catalonia. RESULTS For a given pharmaceutical, two questionnaires identify and score following four variables related to main uncertainties involved: (1) efficacy/effectiveness uncertainty; (2) budget uncertainty; (3) budget impact; and (4) incremental cost-effectiveness ratio (ICER) and willingness to pay. Final score guides the best type of agreement to be implemented accordingly. CONCLUSIONS The steps outlined in this first guidance in Spain, although not compulsory, will provide useful practical tips for how to go about setting up an RSA or PRS in Catalonia (Spain). This guide is not a substitute for suitable regulatory or legal advice.