He has denied any wrongdoing by his wife, Begoña Gómez, and dismissed the allegations as part of a right-wing smear campaign against his leftist government.
But the case has stoked acrimony in Spanish politics, with the conservative opposition calling on him to resign.
Gómez is being investigated for alleged influence peddling and corruption following a complaint filed by an anti-graft NGO with links to the far right called "Manos Limpias" -- Spanish for "Clean Hands".
Judge Juan Carlos Peinado, who is heading the inquiry, is scheduled to question the Socialist premier as a witness at his official residence at 11:00 am (0900 GMT).
The only other time a sitting Spanish prime minister had to testify in a judicial case was in 2017, when Mariano Rajoy was summoned in a graft case that led to the conviction of several members of his conservative Popular Party (PP).
Sánchez asked to testify in writing as is allowed under Spanish law for top government officials, but Peinado rejected the request, arguing he would quiz him as Gómez's spouse.
The premier can now choose to remain silent but "politically this could look bad", said University of Alicante criminal law professor Bernardo del Rosal.
"Not answering the judge, or answering in writing, could create the image that he is arrogant," Del Rosal told AFP.
'Noise'
Gómez, who has worked in fundraising for years, invoked her right to remain silent under questioning by the judge earlier this month.
She is alleged to have used her husband's position as leverage within her professional circles, notably with businessman Juan Carlos Barrabés, who was seeking public funding.
In his testimony, Barrabés - who teaches part of a master's course at Madrid's Complutense University that is run by Gómez - acknowledged meeting her five or six times at Moncloa, the premier's official residence.
Sánchez was also present at two of those meetings, he said.
Barrabés - who got two letters of recommendation from Gómez before pitching for a public tender worth several million euros - said they only talked about matters of innovation, judicial sources said.
Manos Limpias has said its allegations against Gómez were entirely based on media reports, which could turn out to be false.
Spanish prosecutors have failed to get the case dismissed.
Even if a court eventually decides to shelve the case without a trial, "all this noise" will damage the PM's image, Del Rosal said.
'Rally support'
Sánchez's supporters have accused Peinado, whose daughter is a PP city councillor, of political bias.
The judge has taken controversial decisions seen as being in sync with the right, such as in 2015 when he accepted another complaint from Manos Limpias over tweets made by two leftist Madrid city councillors deemed offensive.
Peinado will allow a lawyer from the far-right party Vox to question Sánchez as part of the probe.
Vox is taking part in the investigation as a so-called "popular prosecutor" -- a set-up under Spanish law that allows citizens or organisations to be an accuser in court.
When the probe was opened in April, Sánchez took five days off to consider his future but ultimately stayed on.
Federico Santi, senior analyst for Europe at Eurasia Group, said Sánchez "is leveraging the issue to rally support within his left-wing base with some success".
Sánchez, who has been in office since 2018, has struggled to pass legislation since he returned to power last year after an inconclusive election.
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