Watford Junction, Bushey and Kings Langley railway stations will be closed this bank holiday weekend as a large-scale rail improvement programme gets underway.
The railway line between the Watford and London Euston will be closed from Friday, May 3 to bank holiday Monday, with no trains operating south of Hemel Hempstead.
The Abbey Flyer line will also closed for the weekend due to the works.
Rail replacement busses will be operating over the weekend from the bus station area at the front of Watford Junction.
London Midland passengers will be able to use their tickets on other operators such as Chiltern Railways, First Capital Connect, East Midlands Trains, London Overground and certain London Underground routes.
The closure is the first of eight due to take place between this weekend and next April as part of an £81m project to upgrade the railway lines around Watford
The next closures will be between Saturday, August 9, and Monday 11, then Saturday, August 16 to Monday 18 and then Saturday, August 23 to Tuesday 26.
There will also be a Christmas closures between Wednesday, December 24, and Monday, December 29.
The final closures will be from Saturday, February 14, to Monday 16, then Saturday, February 21, to Monday 23 and then between Friday, April 3, 2015, and Tuesday, April 7.
Dyan Crowther, route managing director for Network Rail, said: "The section of track at Watford is one of the most intensively used, high-speed sections in the UK and has seen tremendous growth in traffic and passengers over the last five years.
"There is never a good time to close the railway but this work is essential to maintain reliable train services for the millions of passengers who travel on this route every year.
"We have worked with all our industry partners to provide passengers with information in advance and will continue to during the work to minimise disruption as much as possible."