Background Cost of illness (COI) studies are carried out under conditions of uncertainty and with incomplete information. There are concerns regarding their generalisability, accuracy and usability in evidence-informed care.Aims A hybrid methodology is used to estimate the regional costs of depression in Catalonia (Spain) following an integrative approach.Methods The cross-design synthesis included nominal groups and quantitative analysis of both top-down and bottom-up studies, and incorporated primary and secondary data from different sources of information in Catalonia. Sensitivity analysis used probabilistic Monte Carlo simulation modelling. A dissemination strategy was planned, including a standard form adapted from cost-effectiveness studies to summarise methods and results.Results The method used allows for a comprehensive estimate of the cost of depression in Catalonia. Health officers and decision-makers concluded that this methodology provided useful information and knowledge for evidence-informed planning in mental health.Conclusions The mix of methods, combined with a simulation model, contributed to a reduction in data gaps and, in conditions of uncertainty, supplied more complete information on the costs of depression in Catalonia. This approach to COI should be differentiated from other COI designs to allow like-with-like comparisons. A consensus on COI typology, procedures and dissemination is needed.