Despite Real strengthening its squad and Atletico losing key assets in recent months, the balance of power in Madrid is tilted toward the underdogs.
Atletico has already beaten Real to the Spanish Super Cup and last season's surprise champions showed that last season's league win at the Santiago Bernabeu Stadium was no fluke by prevailing 2-1 in Saturday's derby.
And that's without star striker Diego Costa, who scored a hat trick for new club Chelsea in a 4-2 win over Swansea. Across London, title rivals Arsenal and Manchester City drew 2-2 in the Premier League.
Here's the pick of the action from across Europe on Saturday:
Losing the domestic title last season was offset at Real Madrid by beating Atletico in the Champions League final. But the $140 million spent on Toni Kroos and James Rodriguez in the offseason couldn't prevent another home humbling by Atletico.
Tiago Cardoso headed Atletico in front only for Cristiano Ronaldo to earn a penalty and then equalize from the spotkick. But Atletico's second-half domination was rewarded with Arda Turan's goal that moved the team four points ahead of Real.
"We have to analyze this problem and try to solve it quickly," Madrid coach Carlo Ancelotti said.
Barcelona, though, is the early front-runner, two points ahead of Atletico. Neymar came off the bench to open his account for the season, scoring twice from Lionel Messi's passes to clinch a 2-0 victory over Athletic Bilbao.
Chelsea finally seems to have found the solution to its striking struggles. Costa took his goal haul to seven in four matches with the treble against Swansea while Loic Remy also scored on his debut since joining from Queens Park Rangers.
Chelsea's fourth win in four matches ended Swansea's perfect start to the Premier League season.
Just how much a team relies on a lethal striker is clear at Liverpool, which was beaten 1-0 by Aston Villa. Gabriel Agbonlahor inflicted Liverpool's second loss in four games since last season's runners-up sold Luis Suarez to Barcelona.
At the Emirates Stadium, Sergio Augero exploited gaps in the Arsenal defense to meet Jesus Navas' cross and put Manchester City ahead in the first half. Jack Wilshere inspired Arsenal's recovery in the second half, chipping the ball over goalkeeper Joe Hart and then heading to Alexis Sanchez to volley into the net. But champion City leveled thanks to the hosts' poor defending when Martin Demichelis headed in from a corner.
Like Arsenal, north London rival Tottenham also conceded late to draw 2-2 at Sunderland. Southampton claimed the biggest victory of the day, a 4-0 rout of Newcastle that makes manager Alan Pardew's future look increasingly precarious.
Roberto Martinez was relieved after Everton won for the first time this season — a 2-0 triumph over West Bromwich Albion. Leicester had been waiting a decade for a topflight win until the newcomers won 1-0 at Stoke. But Burnley remains winless since gaining promotion after Scott Arfield missed a penalty in a 0-0 draw at Crystal Palace.
Back at Borussia Dortmund after an unhappy two-year spell at Manchester United, Shinji Kagawa contributed one of the goals in a 3-1 win over Freiburg.
Bayern Munich was made to work for its second win from three Bundesliga games, with Mario Goetze and Franck Ribery scoring in a 2-0 victory over Stuttgart.
Another lackluster performance by Paris Saint-Germain saw the champions held 1-1 by Rennes. Although unbeaten in the league, PSG has won only twice in five games.
Despite Zoumana Camara put PSG in front before half time, Paul-Georges Ntep leveled after the break for Rennes.
It's two wins out of two in Serie A for Massimiliano Allegri as Juventus manager after Carlos Tevez and Claudio Marchisio clinched a 2-0 victory over Udinese.
Roma also maintained its perfect start to the fledgling season with a 1-0 win at Serie A newcomer Empoli.