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William Shepard Wetmore was born in St. Albans, Vermont, on January 26, 1801. At a young age, he moved to Middletown, Connecticut, to live with his aunt and uncle, attend school, and work in his uncle's shop. At the age of fourteen, he entered the mercantile business in the employ of Edward Carrington & Co. of Providence, Rhode Island. In 1823, Wetmore sailed as the firm's supercargo on the ship Lion, bound for the port of Valparaiso, Chile. He was shipwrecked on the way, but this misfortune soon became an opportunity. Wetmore joined in a partnership with Valparaiso import merchant Richard Alsop, who was originally from Middletown. The firm Alsop & Wetmore conducted trade with the United States and England with great success. In 1825, the partners joined Philadelphia native John Cryder and Alsop, Wetmore & Cryder. This continued until 1829, when Wetmore retired and returned to the United States with a large fortune.

After several years at home while recovering from poor health, William Wetmore departed for Canton, China in 1833. William Wetmore and Samuel Archer, a family friend, completed an agreement to establish Wetmore & Co., a partnership between Wetmore and Archer's son Joseph. Wetmore's cousin, Samuel Wetmore, Jr., would serve as clerk. The elder Archer had close connections to the British textile trade, especially James Brown & Co. of Leeds. John Cryder, who was then working for the London bankers Morrison & Cryder, secured these accounts for Wetmore & Co. With these textile accounts and Joseph Archer's established connections in the tea trade, Wetmore & Co. acquire much of the business previously held by Dunn & Co., a recently disbanded China trade firm. Wetmore & Co. conducted brisk business throughout the 1830s trading in Chinese tea, silk, opium, and other goods to merchants in the United States, Britain, France, Chile, Peru, and Sumatra.

In 1839, Wetmore left China and established himself in New York City. His partner from Chile, Richard Alsop, had been the United States agent for Wetmore & Co. of Canton; however, due to a quarrel, Alsop was removed from the firm. Wetmore then became the principal United States agent for his own Canton firm. In 1844, William Wetmore and John Cryder established the New York City commission merchant firm of Wetmore, Cryder & Co. Cryder had married Wetmore's sister and had recently returned from London. Wetmore, now established in New York, left his cousin, and former clerk, Samuel Wetmore, Jr. as head of the Canton firm Wetmore & Co. William Wetmore removed himself from all business in 1847 and retired to his mansion, Chateau-sur-Mer, in Newport, Rhode Island.

Wetmore traveled from China to London, England, in 1837 to marry his cousin, Esther Phillips Wetmore of Middletown. She was the daughter of his uncle Samuel Wetmore. Esther died in October 1838, a few weeks after the birth of their firstborn daughter. William was then in Canton, and received word of his wife's death through a letter in this collection (see Box 2, folder 25). In 1843, William later married Anstiss Derby Rogers, daughter of Salem, Massachusetts, merchant John Rogers. They had three children with Anstiss: William Shepard Wetmore, Jr. (1844-1858), George Peabody Wetmore (1846-1921), and Annie Derby Rogers Wetmore (1848-1884). Willliam Wetmore died on June 16, 1862.