| First side to vote | 18 |
| First sign | 10 |
| First sign of a highway headache | 32 |
| First sign of fall | 18 |
| First sign of rain | 18 |
| First sign of spring | 20 |
| First sign of spring? | 21 |
| First sign of the zodiac | 24 |
| First sign, astrologically | 26 |
| First signs | 11 |
| First signs of rain | 19 |
| First Sikh | 10 |
| First sin site | 14 |
| First single released on Apple Records | 38 |
| First sinner | 12 |
| First Sister | 12 |
| First site of Olympic games | 27 |
| First site of the Olympic Games | 31 |
| First site to report on the leaked Donald Sterling tapes | 56 |
| First sitting president to have his photograph taken | 52 |
| First sitting president to visit the West Coast | 47 |
| First six of 26 | 15 |
| First six tracks, say | 21 |
| First six-decade hockey pro | 27 |
| First skipper? | 14 |
| First slayer | 12 |
| First small bite | 16 |
| First soft drink sold in a can | 30 |
| First soft drinks sold in cans | 30 |
| First Solo appearance | 21 |
| First son | 9 |
| First son of a President to become President | 44 |
| First son of Eliz. | 18 |
| First son of Eliz. II | 21 |
| First son of Seth | 17 |
| First Son of the '80s | 25 |
| First son, often | 16 |
| First son, sometimes | 20 |
| First Song of the Year Grammy winner | 36 |
| First song on "More of the Monkees" | 45 |
| First song on a CD | 18 |
| First song on a John Lennon album of the same name | 50 |
| First song on an album | 22 |
| First song on an album, perhaps | 31 |
| First song on Genesis's "Genesis" album | 53 |
| First song on Radiohead's "OK Computer" | 53 |
| First song on the Beatles' "White Album" | 54 |
| First soprano to star in "Turandot": 1926 | 51 |
| First sound in an M-G-M film | 28 |
| First sound in an MGM movie | 27 |
| First sound in an SOS call | 26 |
| First sound of an MGM movie | 27 |
| First sound of impact? | 22 |
| First sound of silence? | 23 |
| First sound of work | 19 |
| First South Korean president | 28 |
| First sovereign of Great Britain | 32 |
| First Soviet leader | 19 |
| First Soviet premier | 20 |
| First space travelers | 21 |
| First space travelers from U.S. | 31 |
| First spacecraft to orbit Jupiter | 33 |
| First spacecraft to reach Uranus and Neptune | 44 |
| First spaceman | 14 |
| First spaceman's first name | 31 |
| First spacewoman | 16 |
| First Spanish actor to win an Oscar | 35 |
| First speaker in "Macbeth" | 36 |
| First specimen of a new species | 31 |
| First spin-off from "All in the Family" | 49 |
| First spin: mixed fruit | 23 |
| First spoken word in Genesis | 28 |
| First sporting company to sponsor an African-American | 53 |
| First sports commentator to receive an Emmy | 43 |
| First sports movie to win Best Picture | 38 |
| First square of some board games | 32 |
| First squirt of milk | 20 |
| First st. | 9 |
| First st. admitted to the union in the 20th century | 51 |
| First st. to join the Union after the end of the Civil War | 58 |
| First st. with women voters | 27 |
| First stabber of Caesar | 23 |
| First stage | 11 |
| First stage of a study | 22 |
| First stage of grief | 20 |
| First stages | 12 |
| First stakes | 12 |
| First star ever photographed, 1850 | 34 |
| First starter home? | 19 |
| First State | 11 |
| First state admitted to the Union from the Northwest Territory | 62 |
| First state capital | 19 |
| First state governor of Virginia | 32 |
| First State's capital | 25 |
| First State: Abbr. | 18 |
| First state? | 12 |
| First steamship to cross the Atlantic | 37 |
| First steamship with a planned circumnavigation of the globe | 60 |
| First Steely Dan album to win a Grammy | 38 |
| First step | 10 |