Gender, social conditions, and health throughout the life course affect functional health in later life. This article addresses two specific hypotheses: i) life-course social and health conditions are associated with frailty; and ii) differential exposure and/or vulnerability of women and men to life-course conditions may account for gender differences in frailty. Data originated from a cross-national survey of older adults living in five large Latin American cities. Frailty was defined as the presence of three or more of five criteria: unintentional weight loss (10 pounds during the past year), self-reported exhaustion/poor endurance, weakness (grip strength), limitations in lower extremities, and low physical activity; a prefrail state was defined as the presence of one or two of the above criteria. Associations between frailty and social and health indicators were examined using a proportional odds ordinal logistic regression. Prevalence of frailty varied from 0.30 to 0.48 in women and from 0.21 to 0.35 in men. Childhood (hunger, poor health, and poor socioeconomic conditions), adulthood (little education and non-white-collar occupation), and current social conditions (insufficient income) were associated with higher odds of frailty in both men and women. Comorbidity and body mass index were related to frailty, but their effects differed in women and men. Male/female age-adjusted odds of frailty varied from 1.55 (Bridgetown) to 2.77 (Havana). Differential exposure and vulnerability partially explained differences between women and men. Theoretical models to explain gender and social differences in frailty should use a life-course perspective.