The fourth route, the most southerly of the four, has been largely abandoned east of Warrington; the remaining section caters mainly for freight trains.

During weekday peak times, two daily return trains operate between Liverpool Lime Street and Manchester Victoria, one service in the morning and one in the evening, calling at all stations.

A parliamentary service operates between Ellesmere Port and Liverpool via the western section of the Chat Moss route, calling at all stations between Earlestown and Lime Street.

Local trains also ran to Manchester via Leigh, but these services ceased in 1969 when the Eccles-Tyldesley-Leigh-Kenyon branch was closed as a result of the Beeching Axe.

The northern Liverpool to Manchester line has also seen regular use over the years for diverted services from the West Coast Main Line when parts of the latter have been closed for engineering work, but diversions via Manchester instead have now become more common as they do not involve the train reversing, as would be necessary at Edge Hill, following the electrification of the route.

[5] From 5 March 2015, Class 319 trains started electric operation on this route from Liverpool to Manchester Airport via the Oxford Road viaduct.

[7] TransPennine Express Class 185 DMUs which formerly operated the Manchester Airport - Glasgow/Edinburgh service are now being redeployed to other routes.

[9][10] Now that the electrification of the line is complete and electric services are running, the journey time between Liverpool and Manchester has been reduced from around 45 minutes to 30 minutes due to the greater acceleration achieved by electric trains and the raising of the speed limit along the line from 75 to 90 mph.

[11] Electrification also offers electric haulage options for freight trains, giving a secondary route to the West Coast Main Line from Liverpool.

The Liverpool to Warrington section of this line was initially scheduled to be on the Merseyrail electric urban network.

The Strategic Plan for the North West, the SPNW, in 1973 envisaged that the Outer Loop which was to be an orbital line circling the city of Liverpool, the Edge Hill Spur which is a tunnel connecting the east of Liverpool to the central underground sections, and the lines to St. Helens, Wigan and Warrington would be electrified and all integrated into Merseyrail by 1991.

The Liverpool City Region Combined Authority announced in July 2021 that trials of battery-electric Class 777 trains had been successful with the new units able to travel up to 20 miles on batteries.

This opens up the possibilities of the trains being used to serve Warrington from Liverpool on this line, conforming to the original Merseyrail plan.

TransPennine Express also operate a fast hourly service using this line from Liverpool Lime Street to Cleethorpes - this was extended from Manchester Piccadilly in December 2022.

In the past, the CLC route was used by a variety of local services in addition to limited-stop expresses between the two cities.

The diversion of Liverpool-bound trains to Lime Street in 1966 and the closure of Manchester Central in 1969 (all trains subsequently running to Oxford Road and Piccadilly) saw the route downgraded in importance and from then until the mid-1980s it was operated as a self-contained route due to congestion issues at the Manchester end.

The route from Liverpool to Manchester via Newton le Willows has been popular in recent years with steam locomotive-worked excursion trains.

The Liverpool half is fast third rail electric and the Manchester side slower diesel traction.

However, for passengers who live near to the stations in the middle section of the line it may prove a quicker journey into Liverpool or Manchester.

A further southerly route, using what was St Helens and Runcorn Gap Railway and Warrington and Stockport Railway, connected Liverpool Lime Street with Manchester Oxford Road via Ditton Junction (south west of Widnes), Warrington Bank Quay (low level platforms) and Timperley (north of Altrincham).

The fastest recorded run was from Manchester Exchange to Liverpool Lime St in 30 minutes 46 seconds by a 1936 built Jubilee 5707 with 7 coaches.