In 1604-06, Middleton commanded the second expedition of the British East India Company to the Spice Islands, or the Moluccas, in the East Indies Indonesia to try to lever some influence with the locals as the Dutch East India Company had established a virtual monopoly on the lucrative trade in nutmeg, mace, cloves and pepper. After a successful voyage, Middleton was knighted on his return to England. In 1610, he set off on another voyage for 'The Company', this time with instructions to call at the Red Sea ports and at Surat in western India. At the port of Al-Mukha, or Mocha, in present-day Yemen, his ships and men were seized by the Turkish governor of the region. Middleton and several sailors were imprisoned for six months until they escaped. They managed to rejoin their ships and sailed to India and ultimately, the East Indies where, exhausted, Middleton died in 1613.