This series consists of letters written by Harrison, the majority of which are typewritten carbon copies or drafts, although there are also a few signed originals, some of which are handwritten. Most of the letters from 1921-1928 were written to his children, Carter H. Harrison V (1890-) and Edith Ogden Harrison Manierre (1896- ) (who is referred to as "Ogden"), about Harrison's trips around the world and other overseas travels. Many of these letters are several typewritten pages long. Besides his family correspondence, there are also a number of letters relating to Harrison's post-mayoral political activities, such as letters in which he states his position on a particular issue, supports someone for an elected or appointed position, or reports to the National Democratic Party on the political activity and sentiment in Chicago and other parts of northern Illinois around the time of the 1936 and 1938 elections.

This series also includes: (a) letters relating to the Chicago Municipal Art Commission (1915); (b) letters relating to Harrison's work with the American Red Cross in France (1918-1919); (c) letters about art and Harrison's art collection (e.g., 1929, 1941-1944); (d) letters to Harold L. Ickes, Secretary of the Interior, regarding the Illinois State Advisory Board of the Public Works Administration, of which Harrison was chairman (1933-1934); (e) letters relating to Harrison's position of Collector of Internal Revenue, particularly with respect to patronage job appointments (1934-1944); (f) letters about Harrison's books, Stormy Years (1935-1937), Growing Up With Chicago (1938-1941, and 1944), and With the American Red Cross in France, 1918-1919 (1940, 1944, 1947-1949, and 1951); (g) letters about early Chicago people, places, and events (1936-1945, 1947, and 1949); (h) letters about fly fishing and hunting (1940, 1944-1945, and 1949); (i) letters about stamp collecting, vermouth and other drinks, William Preston Harrison's trips to the South Pacific in the mid-1890s, and various other reminiscences (1942); (j) letters relating to the length of the lines at the Internal Revenue Service payment windows (1943); (k) letters regarding his gifts of prints, books, and papers to Yale University (1947-1949); and (l) letters relating to Harrison's gifts to the Art Institute of Chicago (1932-1949).

Some of the items in this series have handwritten annotations by Harrison explaining the letter's context or giving his thoughts on the sender or the letter's subject. Most of the items in this series date from 1920-1949. There are very few letters from 1873-1910, 1916-1917, and 1950-1953. After 1934, a fair percentage of the letters in this series were written to Harrison's close friends Edgar Lee Masters and Russell MacFall.