cuellar was traded along with ron taylor to the houston astros for hal woodeshick and chuck taylor at the june 15 trade deadline in . upon joining the starting rotation in 1966 for the astros, cuellar won his first six decisions. the last of them was a 3–2 complete game over the cardinals at the astrodome on june 25, in which he recorded a career-high 15 strikeouts. in his final start of the campaign, a 4–3 road win over cincinnati in the second match of a september 28 twi-night doubleheader, he hit his first major-league home run off of sammy ellis to lead off the top of the fifth. cuellar finished at 12–10, with a 2.22 earned run average (era) which was second in the national league to sandy koufax's 1.73.