Hamilton missed out on his 100th career pole in Portugal last Saturday by just seven-thousandths of a second to team-mate Valtteri Bottas.
The Briton teed himself up for a second bite of the cherry at Barcelona's Circuit de Catalunya by setting the fastest time in FP2 with a lap of one minute 18.170secs to finish 0.139s ahead of Bottas.
With an eight-point lead over Red Bull's Max Verstappen going into the fourth race of the season, Hamilton will have been left surprised to see the Dutch driver languishing in ninth place on the timesheet.
During the low-fuel qualifying simulation runs, Verstappen was forced to abort his first flying lap on the soft tyres after making an error at the reprofiled turn 10.
Given the recent discussions around Verstappen's minor mistakes in exceeding track limits this season that have cost him dearly, this was another small error to again blot his copybook.
Verstappen finished 0.615s behind Hamilton, while team-mate Sergio Perez fared no better as the Mexican was a further 0.133s down in 10th place.
In between the Mercedes and Red Bull pairs were a surprising collection of drivers, with Ferrari's Charles Leclerc delivering a fine practice performance to finish 0.165s down on Hamilton, with team-mate Carlos Sainz down in eighth, half-a-second back.
Leclerc was followed by Alpine duo Esteban Ocon and Fernando Alonso, who were separated by just 0.052s, with AlphaTauri duo Pierre Gasly and Yuki Tsunoda sixth and seventh on the timesheet, and closer still as they were split by 0.026s.
Tsunoda endured an uncomfortable moment, though, as he ran wide over the kerb at turn nine 20 minutes into the hour-long session which switched off his AT02, although he managed to limp back to the pits.
Aston Martin's Sebastian Vettel, sporting the revised floor on the AMR21 that was on the car of team-mate Lance Stroll in Portugal, was 11th quickest, 0.777s down.
Worryingly for McLaren, Lando Norris and Daniel Ricciardo were only 12th and 15th, and that after the Briton had been the best of the rest behind Bottas, Verstappen and Hamilton in FP1.
Kimi Raikkonen, who sat out first practice in favour of reserve Robert Kubica who ended the session in the gravel, was 16th and only a second adrift, highlighting the close-knit nature of the field.
George Russell, who had made way for test driver Roy Nissany in FP1, was then seven-tenths of a second back in 17th, followed by team-mate Nicholas Latifi and Haas duo Mick Schumacher and Nikita Mazepin.
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