El Bulli, near Rosas, regained the title it won at the inaugural World's 50 Best Restaurants awards in 2002, swapping places with last year's top eatery, The Fat Duck, in the village of Bray, west of London.
The Spanish restaurant, which one British newspaper critic once described as "culinary nirvana", has consistently been in the top three ever since with its experimental, scientific approach to cuisine known as molecular gastronomy.
Disciples of the food science typically use centrifuges, liquid nitrogen, microscopes or lasers to cook.
El Bulli is said to be booked for months in advance by diners eager to sample 43-year-old chef Ferran Adria's Michelin three-star cooking which includes dishes such as barnacles with tea foam and grilled vegetables with charcoal oil.
The luxury restaurant is only open from April to September to allow Adria to spend the other six months of the year perfecting recipes in his Barcelona laboratory.
Strong showing by Spain
Spain had a strong showing in the awards, organised by the UK-based Restaurant Magazine and unveiled to the cream of the culinary world at a ceremony at London's Science Museum.
Restaurante Arzak, in San Sebastian, northern Spain, was in ninth position, followed by the highest new entrant and its near neighbour, Mugaritz, at 10, and with Can Fabes, in Sant Celoni, near Barcelona, at 11.
The United States has five restaurants in the top 20, including best restaurant in the Americas for the French Laundry in California in fourth.
France had four, including Chef's Choice for Pierre Gagnaire in Paris, and Britain three.
Italy had one - the highest climber, Gambero Rosso, in Rome at 13 - while Tetsuya in Sydney was voted the best restaurant in Australasia and also took fifth spot.
The best restaurant in the Middle East and Africa was said to be La Colombe, in Cape Town, South Africa. It was 28th on the list.
Hong Kong restaurant Felix, which was last year's sole Asian representative, slipped off the list, although London-based Japanese restaurant Nobu made a strong showing at 12.
South Asian eatery Bukhara in Delhi made it to 46th spot this time around.
The awards are based on assessments made by 560 judges across the world.
Voting was changed this year to prevent a repeat of complaints of a London-bias in the awards after 14 restaurants in the British capital made the top 50 in 2005.
Here is the World's Best Restaurants 2006 winners list:
1 El Bulli, Spain - The Penfold's World's Best Restaurant, Best in Europe
2 The Fat Duck, United Kingdom
3 Pierre Gagnaire, France - Chef's Choice
4 French Laundry, US - Best Restaurant in the Americas
5 Tetsuya, Australia - Best Restaurant in Australasia
6 Bras, France
7 Restaurant Le Louis XV, Monaco
8 Per Se, US
9 Restaurante Arzak, Spain
10 Mugaritz, Spain - Highest New Entrant
11 Can Fabes, Spain
12 Nobu, UK
13 Gambero Rosso, Italy - Highest Climber
14 Gordon Ramsay (Royal Hospital Road), UK
15 Restaurant Alain Ducasse, France
16 Jean Georges, US
17 Le Cinq, France
18 Daniel, US
19 Oud Sluis, The Netherlands
20 Chez Panisse, US
21 El Celler de Can Roca, Spain
22 L'Astrance, France
23 Hof van Cleve, Belgium
24 La Maison Troisgros, France
25 L'Atelier, France
26 Charlie Trotter's, US
27 Le Gavroche, UK - Outstanding Value
28 La Colombe, South Africa - Best Restaurant in the Middle East and Africa
29 Enoteca Pinchiorri, Italy
30 Rockpool, Australia
31 Le Calandre, Italy
32 Le Bernardin, US
33 Noma, Denmark
34 Restaurant Dieter Muller, Germany
35 St John, UK
36 Hakkasan, UK
37 Martin Berasategui, Spain
38 Le Quartier Francais, South Africa
39 Chez Dominique, Finland
40 L'Ambroisie, France
41 Die Schwarzwaldstube, Germany
42 Dal Pescatore, Italy
43 Bocuse, France
44 L'Arpege, France
45 Gramercy Tavern, US
46 Bukhara, India
47 De Karmeliet, Belgium
48 Oaxen, Sweden
49 Comme Chez Soi, Belgium
50 DOM, Brazil