Objective: Recent evidence suggests the existence of a physical activity paradox, with beneficial health outcomes associated with leisure time physical activity, but detrimental health outcomes for those engaging in high level occupational physical activity. This is the first quantitative systematic review of evidence regarding the association between occupational physical activity and all-cause mortality. Design: Systematic review with meta-analysis. Data source: A literature search was performed in electronic databases PubMed, Embase, CINAHL, PsycINFO and Cochrane. Eligibility criteria for selecting studies: We screened for peer reviewed articles from prospective studies assessing the association of occupational physical activity with all-cause mortality. A meta-analysis assessed the association of high (compared with low) level occupational physical activity with all-cause mortality, estimating pooled hazard ratios (HR) (with 95% CI). Results: 2490 unique articles were screened and 33 (from 26 studies) were included. Data from 17 studies (with 193 696 participants) were used in a meta-analysis, showing that men with high level occupational physical activity had an 18% increased risk of early mortality compared with those engaging in low level occupational physical activity (HR 1.18, 95% CI 1.05 to 1.34). No such association was observed among women, for whom instead a tendency for an inverse association was found (HR 0.90, 95% CI 0.80 to 1.01). Conclusions: The results of this review indicate detrimental health consequences associated with high level occupational physical activity in men, even when adjusting for relevant factors (such as leisure time physical activity). These findings suggest that research and physical activity guidelines may differentiate between occupational and leisure time physical activity.