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The route between Berlin and Frankfurt upon Oder was already completed in 1803. The route from there to Breslau was built between 1817 and 1819. In 1824 the route was extended from Breslau until Gleiwitz. The section between Berlin and Hamburg was upgraded to a highway between 1827 and 1830, with its section crossing the Grand Duchy of Mecklenburg-Schwerin representing the first structurally designed road there. The routes Northwest of Hamburg were built in the 1850s. The section from Itzehoe until Bredstedt was finished in 1858.
In 1934 the Fernverkehrsstraßen were renamed into Reichsstraßen (literally in English: Reich's streets), but the numbering remained Reichsstraße 5 or R 5. By the Agreement of Potsdam in August 1945 the section East of the Oder-Neiße Line came under Polish authority and was subsequently renumbered within the Polish system of long-distance routes. After the foundation of the two new German republics in 1949 the section of R 5 within the West German Federal Republic of Germany and in West Berlin became Bundesstraße 5 (literally in English: federal street) or B 5. The section in the East German Democratic Republic (GDR) and East Berlin was given back its former name Fernverkehrsstraße 5 or F 5.
During the division of Germany the F 5 played a crucial role as transit route (German: Transitstrecke) between West Berlin and West German Northern Germany. Transit passengers were not allowed to deviate from the route. In East Berlin F 5 passed the Brandenburg Gate, which became an East Berlin checkpoint within the Berlin Wall on August 13, 1961, but was closed the very next day until December 22, 1989.
F 5 gradually lost its function as transit route to new built autobahns (today's A 19 and A 24) until it was rededicated for intra-GDR traffic only on 21 December 1987. After the unification of East Berlin, the GDR and West Berlin with the Federal Republic of Germany on October 3, 1990, the F 5 was named into Bundesstraße 5 or B 5.