In 2005, he reached the quarterfinals of the 2005 Next Generation Adelaide International, losing to Juan Ignacio Chela. In the 2005 Australian Open he reached the third round, losing to then world no. 2 Andy Roddick in a tough three-setter. At the 2005 SAP Open, he lost in the semifinals to Cyril Saulnier, but earned his third victory over Andre Agassi en route. He reached his second semifinal of the year at the 2005 U.S. Men's Clay Court Championships, but lost to Andy Roddick. He reached his second ATP tour final at the 2005 International Raiffeisen Grand Prix, but lost to Nikolay Davydenko in three sets. At the 2005 French Open and 2005 Wimbledon, Melzer reached the third round and lost to Guillermo Coria on both occasions. He then lost six straight main-draw matches in the 2005 Generali Open to Fernando Verdasco, and the 2005 Rogers Cup, 2005 Western & Southern Financial Group Masters, 2005 Pilot Pen Tennis, 2005 US Open, and 2005 Open de Moselle. He then continued his bad run with second-round loses at the 2005 BA-CA Tennis Trophy, the 2005 Mutua Madrileña Masters Madrid, and the 2005 St. Petersburg Open.