Services were operated by DB Regio Hessen, a wholly owned subsidiary of DB Regio, from the commencement of the 2007 timetable in December 2006 until December 2023 with Bombardier Talent 2 electric multiple units.

The RegionalBahn services on the Gießen – Fredberg – Hanau route (RB 49) are also branded as Mittelhessen-Express.

When Hessische Landesbahn took over operations in December 2023, the existing lines were supplemented with a new Frankfurt – Friedberg – Gießen (– Kirchhain) line (RB 37) as an hourly addition to the RB40/RB41 that stops at all stations between Friedberg and Gießen.

The trains running according to the original Mittelhessen concept only have intermediate stops at Butzbach, Bad Nauheim, Friedberg and Frankfurt West.

Since the takeover by Hessische Landesbahn in December 2023, 32 four and five-car Alstom Coradia Continental electric multiple units (class 1440) have been intended to operate on the route, although this has been delayed by problems with software.