The brothers began 2010 playing at the 2010 Heineken Open in Auckland. However, the pair lost in the first round. They then went on successfully defending their title at the 2010 Australian Open, beating Daniel Nestor and Nenad Zimonjić in the final, thus claiming their fourth Australian Open title and eighth major title. They also defended their titles at the 2010 Delray Beach International Tennis Championships (where they earned their 600th victory as a team) and the U.S. Men's Clay Court Championships in Houston. The brothers participated in the first round of Davis Cup, where they were drawn to face Serbia in Belgrade on clay courts. Mike had to withdraw due to food poisoning and was replaced by John Isner. Bob and Isner won the doubles rubber in five sets against Janko Tipsarević and Zimonjić. However, the US lost the tie 3–2 (with the last rubber being a dead rubber). The brothers then won two back to back Masters Series titles during the European clay tour at the 2010 Internazionali BNL d'Italia in Rome and the 2010 Mutua Madrileña Madrid Open. They defeated compatriots Isner and Sam Querrey in Rome, and co-world No. 1s Nestor and Zimonjić in Madrid. This ended their ATP World Tour Masters 1000 title drought since August 2008 and equalled The Woodies' record of 61 doubles titles.
