This series is primarily made up of letters to and from persons who appear to have been ancestors of Harrison, although there are also a few items (such as a will, letters of introduction, seventeenth and eighteenth century land deeds, and documents concerning military or political appointments), that are not correspondence but which have been included in this series because they relate to Harrison's ancestors. The series also includes: (a) a letter sent to Caroline Owsley from Belle Harvey regarding the Grasshopper Club and other social activities of Harrison's mother, Sophonisba Preston Harrison; (b) three letters sent to William Preston Harrison, Harrison's brother (a response from Rutherford B. Hayes to Preston's request for an autograph, a condolence letter following Harrison's father's assassination, and a thank you note for a complimentary subscription to the Chicago Times); (c) two letters sent by Harrison's son, Carter H. Harrison V, to Russell MacFall following Harrison's death; (d) seventy letters from Ella Lewis to Lucy Brady Cook, Harrison's daughter-in-law; and (e) a letter from James Madison to Robert H. Grayson.

The letters to and from Harrison's ancestors cover a variety of topics, both business and personal, but seem to have been collected by Harrison because they were written by, or sent to, family members, rather than because he was particularly interested in their subject matter. Only a very few of the items in this series contain explanatory annotations by Harrison. Correspondence relating specifically to the genealogy and history of the Harrison Family is gathered in Series 11 (Harrison Family History). Correspondence to or from Harrison's father, Carter H. Harrison III, or Harrison's wife, Edith Ogden Harrison, is arranged separately as well in Series 16-17, and Series 14-15, respectively.