Since becoming Big 12 rivals, West Virginia is 5-1 straight up and 4-1-1 against the spread in the series with Iowa State, with three wins in Ames, Iowa.
The Mountaineers are favored to make it four in a row at Jack Trice Stadium when they battle the Cyclones on Saturday evening.
College football point spread: The Mountaineers opened as 4.5-point favorites, according to sportsbooks monitored by OddsShark. (Line updates and matchup report)
College football betting pick, via OddsShark computer: 31.9-25.2 Mountaineers (College football picks on every game)
Why the West Virginia Mountaineers can cover the spread
WVU is one of the last eight undefeated Power 5 programs this season, following its 38-22 victory over Kansas last week.
The Mountaineers jumped out to a 14-0 lead on the Jayhawks 10 minutes into the game, led 21-7 at the half, let Kansas get within 21-14 but scored the next 17 points to pull away.
West Virginia gave up a Jayhawks touchdown on the final play of the game to create a slightly misleading final score.
The Mountaineers outgained Kansas 509-286, held a 29-16 edge in first downs and won time of possession by a 34/26 split.
West Virginia would have come closer to covering the 27-point spread, but four turnovers inside Kansas territory, including three deep in the red zone, cost the Mountaineers at least 16 points and probably more.
Up until last week, West Virginia was perfect against the spread this season, covering as favorites of 10 points against Tennessee, 33 against Youngstown State, 15 against Kansas State and four against Texas Tech.
Why the Iowa State Cyclones can cover the spread
Iowa State bounced back from a tough loss at TCU two weeks ago to upset Oklahoma State on the road in Stillwater last week 48-42.
The Cyclones spotted the Cowboys the first seven points of the game, then scored the next 16 and led 30-21 at the half. ISU then twice allowed OSU to pull within one score in the second half but answered back both times and hung on for the outright victory as a 10-point dog.
Iowa State posted 465 yards of total offense, led by third-string quarterback Brock Purdy, who threw for 318 yards and four touchdowns and ran for 84 and another score. Meanwhile, the Cyclones defense held the Big 12's leading rusher, Justice Hill, to just 66 yards on 24 carries, and the special teams blocked an Oklahoma State punt for a safety.
Iowa State is now 4-5 SU and 7-2 ATS its last nine games against ranked opponents.
Smart betting pick
West Virginia is coming off a sub-par performance against an inferior foe last week, while Iowa State is coming off a big effort in a conference road victory.
But the Mountaineers should be sharper this week, while the Cyclones might be ripe for a letdown. The smart money here gives the points with West Virginia.
College football betting trends
The total has gone under in three of West Virginia's last four games versus Iowa State.
The total has gone under in 10 of Iowa State's last 13 games.
Iowa State is 12-37 SU in its last 49 games versus its conference.
All college football odds and betting trends according to Bleacher Report's official odds partner, OddsShark. Check out OddsShark on Twitter and Instagram or head to YouTube for more betting picks and analysis on this week's top games. You can also download the free odds tracker app.