On what will be May's first visit to Spain since becoming prime minister in July, the British premier will hold a working lunch with Mariano Rajoy, the interim leader following two indecisive general elections.
On the agenda is a dual pledge committing to work to protect the rights of both Spanish citizens living in the UK and the huge number of British expats living in Spain.
In the wake of comments from Spain's foreign minister Jose Manuel Garcia-Margallo, May is likely to reiterate the British government stance that sovereignty over Gibraltar is firmly off the table when it comes to negotiating over Brexit terms.
Spain has formally invited the UK to discuss joint sovereignty over the Rock to allow Gibraltar to maintain access to the European Union, a proposal swiftly rejected by both the Gibraltar and British governments.
The Madrid visit is part of a whistle-stop tour of EU to garner support ahead of Brexit negotiations when the UK invokes Article 50 in the spring.