Slow walking speed is associated with increased mortality in the elderly, but it is unknown whether a similar association is present in late midlife. Our aim was to examine walking speed in late midlife as a predictor of mortality, as well as factors that may explain this association. Data are drawn from the Whitehall II longitudinal cohort study of British civil servants. The analyses are based on 6,266 participants (29% women; mean age = 61 years, SD = 6) for whom “walking speed at usual pace” was measured over 8 ft (2.44 m) at baseline. Participants were followed for all-cause and cause-specific mortalities during a mean of 6.4 (SD = 0.8) years. During this period, 227 participants died. Participants in the bottom sex-specific third of walking speed (men, <1.26 m/s; women, <1.09 m/s) had an increased risk of death compared to those in the middle and top thirds (age- and sex-adjusted hazard ratio = 1.89, 95% confidence interval (CI) = 1.45–2.46), with no evidence of effect modification by age or sex (interactions, P ≥ 0.40). The association between walking speed and mortality was partially explained by baseline inflammatory markers (percentage reduction of the association 22.8%), height and body mass index (16.6%), chronic diseases (14.0%), and health behaviors (13.4%). Together these and other baseline factors (socioeconomic status, cardiovascular risk factors, cognitive function) explained 48.5% of the association (adjusted hazard ratio = 1.39, 95% CI = 1.04–1.84). In conclusion, walking speed measured in late midlife seems to be an important marker of mortality risk; multiple factors, in particular inflammatory markers, partially explain this association. Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9387-9) contains supplementary material, which is available to authorized users.