In addition to Everton, Pompey, City and Spurs are at home in the first leg.
Portsmouth's opponents are officially known as Vitoria SC - and Pompey boss Harry Redknapp said: "It is not an easy draw. They are a good side.
"The Portuguese league is a tough one with teams like FC Porto, Sporting Lisbon and Benfica - but Vitoria finished third last season so they can't be bad."
Tottenham director of football Damien Comolli said the London club will have to be carfeul against Polish side Wisla Krakow.
"The second leg will be away. They beat Barcelona the other night," said Comolli.
"They are very passionate fans so we will have to do very well at home to start with. It will be a competitive tie for sure."
Dutch side FC Twente, now coached by former England boss Steve McClaren, will play French club Rennes after their defeat at the hands of Arsenal in their Champions League qualifying tie.
Seven-times European champions AC Milan face Swiss outfit FC Zurich in the opening round while Sevilla, who won the Uefa Cup in successive seasons under coach Juande Ramos in 2006 and 2007, play FC Salzburg of Austria.
The first-leg ties will be played on 18 September with the return legs taking place on 2 October.
The 40 teams that progress from this round will reach the group stage of the competition.
The final takes place on 20 May at the Sukru Saracoglu stadium, the home ground of Turkish club Fenerbahce.
Uefa Cup first-round draw in full:
AC Milan v FC Zurich Politehnica Timisoara v Partizan Belgrade Hertha Berlin v St Patricks Banik Ostrava v Spartak Moscow Metalist Kharkiv v Besiktas Portsmouth v Guimaraes Kayserispor v PSG Sevilla v SV Red Bull Salzburg Wolfsburg v Rapid Bucuresti Sampdoria v FBK Kaunas Maritimo v Valencia Dinamo Zagreb v Sparta Prague Man City v Omonia Nicosia Young Boys v Club Brugge AS Nancy v Motherwell Everton v Standard Liege Napoli v Benfica AC Bellinzona v Galatasaray NEC v Dinamo Bucuresti Racing Santander v FC Honka APOEL Nicosia v Schalke 04 Litex Lovech v Aston Villa FK Austria Magna v Lech Poznan Vitoria Setubal v Heerenveen SK Brann v Deportivo La Coruna Slavia Prague v Vaslui Slaven Koprivnica v CSKA Moscow Brondby v Rosenborg Cherno More v VfB Stuttgart Rennes v FC Twente Ajax v Borac Tottenham v Wisla Krakow FC Copenhagen v FC Moscow MSK Zilina v Levski Sofia Borussia Dortmund v Udinese Braga v Artmedia Petrzalka Feyenoord v Kalmar FF Hamburg v Unirea Urziceni Hapoel Tel-Aviv v Saint Etienne FC Nordsjaelland v Olympiacos
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