It is the westernmost north–south "reference road", running from Greenock in Scotland, south through Great Britain and France to Algeciras, Spain.

The E5 follows the route Greenock – Glasgow – Gretna – Carlisle – Penrith – Preston – Warrington – Birmingham – Oxford – Newbury – Southampton ...

Le Havre – Paris – Orléans – Tours – Poitiers – Bordeaux – San Sebastián – Burgos – Madrid – Córdoba – Seville – Cádiz – Algeciras.

The E5 crosses the French border at Irun, it passes the major cities of San Sebastián, Vitoria-Gasteiz and Burgos before it arrives at the nation's capital Madrid.

It continues south of Madrid towards Andalusia, passing Córdoba, Seville, Jerez de la Frontera and Cádiz to end at the port city of Algeciras.