Physical inactivity may exacerbate the adverse health effects associated with shift work. We investigated the association of shift work with leisure-time physical inactivity (LTPI). A cross-sectional analysis included 33 983 adults from National Health Interview Survey who self-reported their work schedule and leisure-time physical activity. Participants were classified in to two groups as either (a) inactive or (b) insufficiently/sufficiently. Prevalence ratios were derived using SUDAAN. Analyses were stratified by sex. In this sample of U.S. workers, 27% were shift workers, 26% were physically inactive, and 47% did not meet recommended levels of leisure-time physical activity. Inactivity level was 23% higher in women than in men among shift workers but did not differ by sex among daytime workers (PR = 1.02, 95% CI: 0.96-1.07). Evening or night work was associated with higher LTPI among women but not men. LTPI was 17% higher in women working the night shift, and 24% higher in those on the evening shift compared to those working the daytime shift. These findings suggest that shift work may contribute to increased LTPI, with effects that may be particularly pronounced in women. Interventions addressing LTPI among shift workers may help mitigate the adverse health effects that have been linked to shift work in prior studies.