| First semester offerings | 24 |
| First self-propelled spaceman | 29 |
| First self-propelled astronaut | 30 |
| First seducer | 13 |
| First section of a tome | 23 |
| First section of a textbook, for short | 38 |
| First section | 13 |
| First secretary of war | 22 |
| First Secretary of Transportation | 33 |
| First secretary of Homeland Security | 36 |
| First secretary of H.E.W., 1953, ___ Culp Hobby | 47 |
| First Secretary General of the U.N. | 35 |
| First second son | 16 |
| First Sec. of Transportation: 1966 | 34 |
| First season | 12 |
| First Seahawk quarterback Jim | 29 |
| First Scorsese/DeNiro collaboration | 35 |
| First schizophrenic problem? | 28 |
| First schizophrenicproblem? | 28 |
| First sch. to win 100 NCAA championships, across all sports | 59 |
| First sch. | 10 |
| First satellite to transmit a phone call through space, 1962 | 60 |
| First satellite | 15 |
| First saint canonized by a pope | 31 |
| First Russian tsar | 18 |
| First Russian to orbit Earth | 28 |
| First Russian to be called "czar" | 43 |
| First Russian Orthodox saint | 28 |
| First Russian Literature Nobelist Ivan | 38 |
| First Russian Literature Nobelist | 33 |
| First Russian czar | 18 |
| First rung on a ladder | 22 |
| First run of the still | 22 |
| First ruler of the Slavs | 24 |
| First ruler of all Egypt | 24 |
| First rule of lion taming? | 26 |
| First row | 9 |
| First round pick of the Magic | 29 |
| First round of voting | 21 |
| First round exemptions, in tournaments | 38 |
| First round draft pick, perhaps | 31 |
| First roofed ballpark | 21 |
| First romance, often | 20 |
| First Roman to be deified | 25 |
| First Roman emperor | 19 |
| First rock star to appear on a U.S. stamp | 41 |
| First rock from the sun | 23 |
| First rock band whose members received Kennedy Center Honors | 60 |
| First rite | 10 |
| First right-handed batter to reach 500 home runs | 48 |
| First rib-loser | 15 |
| First response to a call | 24 |
| First response orgs. | 20 |
| First responders: Abbr. | 23 |
| First responders, often (abbr.) | 31 |
| First responders, for short | 27 |
| First responders, briefly | 25 |
| First responders, at times | 26 |
| First responders' destinations, briefly | 43 |
| First responders (abbr.) | 24 |
| First responder, say: Abbr. | 27 |
| First responder, perhaps | 24 |
| First responder, often | 22 |
| First responder, maybe | 22 |
| First responder, for short | 26 |
| First responder, briefly | 24 |
| First responder's skill | 27 |
| First responder | 15 |
| First resolution | 16 |
| First resident of the White House | 33 |
| First residence (option 2) | 26 |
| First residence (option 1) | 26 |
| First residence (last option) | 29 |
| First residence | 15 |
| First rescue boat | 17 |
| First Republican VP | 19 |
| First Republican prez | 21 |
| First Republican President | 26 |
| First Republic of Texas president | 33 |
| First rental car company to be located at an airport | 52 |
| First rendering, say | 20 |
| First Reich rulers: 936-1002 | 28 |
| First Reich for short | 22 |
| First refugee named Canadian Prime Minister | 43 |
| First Red Army leader | 21 |
| First recording | 15 |
| First recorded Chinese dynasty | 30 |
| First recipient of the Harvard AIDS Initiative Leadership Award | 63 |
| First Reality Primetime Emmy winner | 35 |
| First reader canine | 19 |
| First razor with a pivoting head | 32 |
| First rate | 10 |
| First rapper to win the Best Original Song Academy Award | 56 |
| First rapper to win an Oscar for Best Original Song | 51 |
| First rapper to win a Best Song Oscar | 37 |
| First rap group to appear on the cover of Rolling Stone | 55 |
| First rank | 10 |
| First radio station | 19 |
| First radio code word? | 22 |
| First rabies vaccine creator | 28 |