Objective To assess the burden and factors associated with highway work-zone (HWZ) crashes. Design Historical cohort. Setting Section of the Karachi-Hala Road, Pakistan (196 km). Data Police-reported crashes and traffic statistics from January 2006 to December 2008. Analysis Crash and death risk between the HWZ and other zones for a 50 km section were compared. Crash locations were described for a further 146 km section on which factors associated with HWZ crashes were assessed. Results HWZ crashes accounted for 15.0% of traffic crashes (N=180) and 30.8% of road fatalities (N=91) on the 196 km section. Rates were higher in the HWZ than other zones for crashes (rate ratio (RR)=2.35, 95% CI=1.17 to 4.70) and deaths (RR=4.70, 95% CI=2.11 to 10.46). Opposite-direction crashes (adjusted OR (aOR)= 10.65, 95% CI=3.22 to 35.25) and traffic crashes involving pedestrians (aOR=6.03, 95% CI=1.39 to 26.20) and on wet surfaces (aOR=7.26, 95% CI=4.15 to 48.89) were significantly associated with the HWZ. Conclusion These results support the introduction of prevention measures such as strict traffic enforcement, traffic separation, improving pedestrian visibility, and hazard signage at HWZs in Pakistan. The feasibility and effectiveness of these measures remains to be evaluated.