This established the legal basis for the line via Marburg, Gießen, and Friedberg through easier terrain to the originally preferred route, but which crossed national boundaries several times.

In the southern sector, the route ran after its exit from the Main–Weser station in Frankfurt approximately parallel with the Taunusstrasse [de] (English: Taunus Street) (at that time, only partly built), along the current streets of Friedrich-Ebert-Anlage and Hamburger Allee to the then Kurhessen town of Bockenheim, now the site of Frankfurt (Main) West station.

The line then went through the Grand Duchy of Hesse town of Boden bis Friedberg, then a piece of Frankfurt-owned territory in Dortelweil.

Bad Nauheim was a Kurhessen enclave within the Grand Duchy of Hesse exclave of Oberhessen through which the line ran to Gießen.

Express trains continued to run from Frankfurt to Berlin via Kassel until the end of World War II.

420,000 square metres (500,000 sq yd) of soil was excavated over a length of 5.7 kilometres (3.5 mi) and relocated at a cost of DM 24.0 million.

[3] Services of Intercity-Express line 26 run on the Main–Weser Railway from Ostseebad Binz or Hamburg-Altona via Kassel and Frankfurt to Karlsruhe at two-hour intervals.

There was also a direct connection to Berlin Südkreuz until the end of 2015, which was the first Intercity service on the line from Monday to Saturday.

Even earlier there were direct long-distance services from Frankfurt via Gießen and Siegen to Hagen Hauptbahnhof and beyond to Münster and Norddeich Mole.

Since December 2006, Mittelhessen-Express services are formed in Gießen from two coupled Regionalbahn trains coming from Treysa and Dillenburg and then together run to Frankfurt at a higher speed.

Since 14 December 2014, two of three services have been operated on weekdays by Kurhessenbahn (a Deutsche Bahn brand) using class 628 diesel multiple unit sets.

FLIRT multiple units operated by Hessische Landesbahn replaced the RegioTrams on line RT 9 at the 2015/2016 timetable change on 13 December 2015.

Talent 2 electric multiple units are used for the hourly Mittelhessen-Express between Frankfurt and Treysa, which are operated by DB Regio Mitte.

[4] Class 143 locomotives occasionally haul modernised Silberling carriages between Gießen and Marburg, Kirchhain and Treysa in the peak hours.

The DB Regional-Express services between Frankfurt and Kassel are almost exclusively operated as double-deck push-pull trains, hauled by Bombardier TRAXX (class 146) locomotives.

At the 2010/2011 timetable change, Hessische Landesbahn (HLB) took over the operation of some services between Frankfurt am Main, Marburg and Siegen, branded as the Main-Sieg-Express, on behalf of the Rhein-Main-Verkehrsverbund (Rhine-Main Transport Association) and the Zweckverband Nahverkehr Westphalen-Lippe (municipal association for local transport of Westphalia-Lippe).

Occasionally, during construction or breakdowns on the Hanover–Würzburg high-speed railway, Intercity-Express services are also diverted between Frankfurt (Main) Hauptbahnhof and Kassel-Wilhelmshöhe, which as a result do not stop in Fulda and Hanau.

Between Frankfurt West and Friedberg, S-Bahn, Regional, and long-distance services and freight traffic share the two tracks of the Main–Weser railway.

[6][7] As a result, the track would be largely equipped with two to six metre-high noise barriers, as a compensatory measure, and an old arm of the Nidda would be restored to a more natural condition.

In November 2011, the Hessian Administrative Court (Hessische Verwaltungsgerichtshof, VGH) dismissed complaints from residents and the citizens' initiative 2statt4 against the planning approval decision and an appeal was not permitted.

[15] This was the location of the operating point of Ginnheim, consisting of an overtaking loop towards Kassel from km 194.0 to 193.2,[17] which was abandoned for the construction of the tracks for the S-Bahn.