Expectancy, age, and sex have been shown to affect reaction time (RT) in a variety of settings; however, the literature contains no studies exploring interactions among these factors using large-scale cross-sectional and longitudinal data. Thus, using data gathered over 17 years in the Baltimore Longitudinal Study of Aging (BLSA), the present study examine the effects of these factors on simple auditory reaction time for 1325 subjects (869 males, 456 females) on their first visit, 620 subjects (473 males, 147 females) for three visits in two-year intervals, and 307 subjects (277 males, 30 females) for five visits with two-year intervisit intervals. Across subjects and visits a fixed schedule of variable inter-stimulus intervals (ISIs) were employed ranging from 6 to 13 seconds (s), analyzed both as ISI and relative ISI (current ISI minus the previous ISI). Data were analyzed cross-sectionally according to decades in an Age8 × Sex2 × ISI8 mixed analysis of variance (ANOVA) design and an Age8 × Sex2 × Relative ISI6 mixed ANOVA design. Longitudinal analyses used similar designs but adjusted the number of age intervals examined as the sample decreased with visits. Results indicated that, as expected, with age came an overall slowing of RT, males were faster than females across decades. There was a relative ISI main effect demonstrating that across conditions, subjects reacted slower to cases in which long foreperiods were followed by short ones. The age by relative ISI interaction revealed that, like Botwinick, Brinley, and Birren (1957), the older subjects, compared to the young, were generally slower in responding and were caught “off guard” when long preparatory interval were followed by short ones. There was also a sex by relative ISI interaction such that the “being caught off-guard” was more pronounced in females than males. The ISI main effect took the form of a “U”, similar to what would be expected in the case of shorter ISIs, such that RT was slowest during the ISI conditions of 6 and 13 s and fastest in the middle. An age by sex by ISI interaction showed that older females had difficulty maintaining their state of readiness and the older males were especially slow when the stimulus occurred well before the general expected time. For longitudinal analyses, the pattern of visit 1–3 corresponds to the pattern of visit 1 almost exactly, but it also shows that there is slowing with repeat visit. In visit 1–5, there is a sex difference pattern of responding. Females have a pattern that progressively slows with repeat visit. But males tend to show increased RT between first visit and second visit, and then there is slight improvement with repeat visit. This study supports the notion that older individual have difficulty maintaining attention or preparedness and are particularly slow when arrival of the stimulus is unexpected or uncertained. A better understanding of set in relation to age has implication for task design, personnel selection, performance prediction, and accident prevention.