The Population Study of Women in Gothenburg, Sweden is an ongoing prospective study of female residents who were recruited from the local registry in 1968-1969 when they were 38-60 years old. The data presented here were collected from 361 healthy women who underwent a baseline physical examination including a supplementary dietary history interview and returned for a second general health examination 6 years later. This report identifies a subgroup of 57 women who were sedentary during their leisure time and appear to have been particularly susceptible to gaining weight as a function of the fat content of their diets. Specifically, longitudinal analysis of body weights in the whole sample revealed a statistical interaction between leisure-time physical activity and habitual dietary fat intake (energy%), as reported at the baseline examination, in the prediction of subsequent weight change. Further stratified analysis suggested that weight changes were significantly dependent on dietary fat intake among the sedentary women only. High energy intake also predicted weight gain in the sedentary group, although the predictive value for a high-fat diet was of marginal significance after adjusting for total energy consumption. These results suggest that sedentary recreational activity plus a low-fat diet may have a combined contribution to weight change that is not equivalent to the sum of the separate effects. Such a synergy between two modifiable lifestyle factors seems highly relevant for prevention of obesity.