| First division of an act | 24 |
| First divorced U.S. president | 29 |
| First Dodge with front-wheel drive | 34 |
| First dog in space | 18 |
| First Dog of the 1940s | 22 |
| First dog to orbit Earth | 24 |
| First dog walker, maybe | 23 |
| First domed ballpark | 20 |
| First Dominican major-league manager | 36 |
| First Dominican manager in MLB history | 38 |
| First Dominican manager in the major leagues | 44 |
| First Dominican-born Major League Baseball manager | 50 |
| First donor? | 12 |
| First double, and first female, Nobelist | 40 |
| First double-digit number | 25 |
| First down? | 11 |
| First Dr. Kildare | 17 |
| First Dracula of film | 21 |
| First draft | 11 |
| First drawer of the Democratic donkey | 37 |
| First drawing | 13 |
| First drawing class, perhaps | 28 |
| First Dreamliner buyer | 22 |
| First drink ever ordered by James Bond | 38 |
| First drink of hot coffee, e.g. | 31 |
| First drug approved to treat AIDS | 33 |
| First duke of Normandy | 22 |
| First Dynasty in Chinese history | 32 |
| First dynasty of Polish rulers | 30 |
| First Earl of Avon | 18 |
| First Earl of Beaconsfield | 26 |
| First Earl of Chatham | 21 |
| First Earl of Leicester | 23 |
| First earth orbiter | 19 |
| First ed. | 9 |
| First edition, usually | 22 |
| First editor of "The Overland Monthly" | 48 |
| First editor of The Atlantic Monthly | 36 |
| First efforts at compromise | 27 |
| First Egyptian king | 19 |
| First elected Congresswoman Jeannette | 37 |
| First elected governor of Alaska | 32 |
| First elected member at Cooperstown | 35 |
| First electronic computer | 25 |
| First electronic stock market | 29 |
| First elements | 14 |
| First Emmy song hit: 1955 | 25 |
| First Emmy-winning song | 23 |
| First emperor of Austria | 24 |
| First emperor of Brazil | 23 |
| First English child born in America | 35 |
| First English colony in America | 31 |
| First English commander to see the Pacific | 42 |
| First English globe-girdler | 27 |
| First English king | 18 |
| First English printer | 21 |
| First entry in ''Who's Who in the Bible'' | 61 |
| First entry in a crossword to a constructor | 43 |
| First episode | 13 |
| First episode in a TV series | 28 |
| First episode of many a series | 30 |
| First episodes | 14 |
| First estate | 12 |
| First European explorer to see New Zealand | 42 |
| First European nation to win the World Cup | 42 |
| First European on Prince Edward Island | 38 |
| First European to cross America | 31 |
| First European to cross the Mississippi | 39 |
| First European to discover Alaska | 33 |
| First European to discover Tahiti | 33 |
| First European to enter New York Bay | 36 |
| First European to land in North America | 39 |
| First European to reach India by sea | 36 |
| First European to reach New Zealand | 35 |
| First European to reach the Pacific | 35 |
| First event in a series | 23 |
| First eviction site | 19 |
| First excuse | 12 |
| First experience | 16 |
| First explorer to sail directly from Europe to India | 52 |
| First extra baseball inning | 27 |
| First extra inning | 18 |
| First fall setting | 18 |
| First Families of Virginia surname | 34 |
| First family | 12 |
| First family as of 2009 | 23 |
| First Family at Albany | 22 |
| First family before the Wilsons | 31 |
| First family father | 19 |
| First family grandson | 21 |
| First family greeting | 21 |
| First family home | 17 |
| First family member | 19 |
| First family member? | 20 |
| First family of 1842 | 20 |
| First family of 1850 | 20 |
| First family of 1910 | 20 |
| First family of 1975 | 20 |
| First Family of 2010 | 20 |
| First Family of Alaska in the 60's | 38 |