He always has a nice smile on his face regardless of who he is with.
It doesn't matter who he is with, he's always smiling.
この場合、次のような言い方ができます。
ーHe always has a nice smile on his face regardless of who he is with.
「彼は誰といてもいつも笑顔だ」
regardless of who he is with で「彼が誰と一緒にいるかにかかわらず」
ーIt doesn't matter who he is with, he's always smiling.
「彼は誰といてもいつも笑っている」
It doesn't matter who he is with ... で「彼は誰が一緒にいても関係ない」
ご参考まで！
Regardless of who he is with, he is always smiling.
He always has a smile on his face, regardless of the person he is with.
ご質問ありがとうございます。
① "Regardless of who he is with,"＝「彼は誰といても」
"he is always smiling."＝「彼はいつも笑顔でいる。」
② "He always has a smile on his face,"＝「彼はいつも顔がニコニコしている」
"regardless of the person he is with."＝「どの人といても。」
ご参考になると幸いです。
カナダ 
アメリカ合衆国 
