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
This page is best viewed in an up-to-date web browser with style sheets (CSS) enabled. While you will be able to view the content of this page in your current browser, you will not be able to get the full visual experience. Please consider upgrading your browser software or enabling style sheets (CSS) if you are able to do so.