The objectives of this study were to estimate the resource use and cost of treating acute cough/lower respiratory tract infection (acute cough/LRTI) in 13 European countries, to explore reasons for differences in cost and to document the challenges that researchers face when collecting information on cost alongside multinational studies. Data on resource use and cost were collected alongside an observational study in 14 primary care networks across 13 European countries and a mean cost was generated for each network. The results show that the mean cost (standard deviation) of treating acute cough/LRTI in Europe ranged from euro23.88 (34.67) in Balatonfüred (Hungary) to euro116.47 (34.29) in Jonkoping (Sweden). The observed differences in costs were statistically significant (P < 0.01). Major cost drivers include general practitioner visits and drug costs in all networks, whilst differences in health systems and regional factors could account for differences in cost between networks. The major barrier to conducting multinational cost studies are barriers associated with identifying cost information.