Fielder signed a $214-million, nine-year deal with Detroit in the offseason, forming a powerful middle of the order with Cabrera that was on full display against Red Sox starter Josh Beckett (0-1).
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Cabrera opened the scoring in the first inning with a two-run shot to left-centerfield, and Fielder hit a solo homer in the fourth to the same part of the ballpark.
Cabrera and Fielder hit back-to-back solo homers in the fifth.
Duane Below (1-0) got the win in relief after Detroit starter Doug Fister left in the fourth with a strain in his left side.
Alex Avila also hit a two-run homer.
It was the 21st multihomer game for Cabrera and the 23rd for Fielder.
Cabrera even showed some impressive reflexes at third base, where he moved this season to make room for Fielder at first. Cabrera lunged to his left to make a diving catch of Jarrod Saltalamacchia's liner in the fifth.
"That was a nice play. Did you see that?" Cabrera said. "Everybody was surprised."
Beckett went to Cleveland earlier in the week to get a second opinion on a thumb injury. He allowed seven runs and seven hits in 42/3 innings, and the five homers he gave up equaled a career high.