The Irons prevailed 1-0 at Southampton on Boxing Day, but it came at a significant cost, as three players were withdrawn with injuries while two picked up suspension-inducing yellow cards.
Max Kilman, Carlos Soler and Lukasz Fabianski - stretchered off after a worrying blow to the head - are the stricken trio in question, while Tomas Soucek and Guido Rodriguez were booked for the fifth time in the top-flight season and cannot take part in this one either.
Lopetegui will therefore need to alter over half of his winning team from Thursday's success on the South Coast, starting with Alphonse Areola standing in for the concussed Fabianski in between the sticks.
Kilman's shoulder problem should lead to a recall for Jean-Clair Todibo at the back, where Aaron Wan-Bissaka, Dinos Mavropanos and Emerson Palmieri can be expected to reprise their roles.
There is one small sliver of good news among the doom and gloom; Lucas Paqueta is back from suspension and will certainly be recalled to the engine room, where Edson Alvarez will also be reintroduced.
Fringe midfielder Andy Irving surely has his best chance of making his full Premier League debut on Sunday, but given his inexperience in the top flight and the calibre of opposition in question, Lopetegui may switch Mohammed Kudus to a central role and draft Crysencio Summerville into the XI.
The former Leeds United man would comprise part of an attack-heavy setup also housing Jarrod Bowen and Niclas Fullkrug, still filling in for Michail Antonio following his road traffic accident.
West Ham United possible starting lineup:
Areola; Wan-Bissaka, Mavropanos, Todibo, Emerson; Alvarez; Bowen, Paqueta, Kudus, Summerville; Fullkrug
Written by
Ben Knapton