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Objective Non-standard work schedules are becoming increasingly prevalent, with one in five workers participating in night shifts. Whether working night shifts is associated with cardiovascular-kidney-metabolic (CKM) outcomes, and whether chronotype or sleep duration modify this association, remains unclear.Material and Methods We utilized data from 96,365 UK Biobank participants (57% female, mean age 62 years), with information on employment history and tracked incidence of CKM (including cardiovascular diseases, chronic kidney diseases and/or type 2 diabetes) through 2022. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs), adjusting for a range of potential confounding factors.Results Based on 5,967 incident CKM cases, participants with more than 20 years of night shift work history had a significantly higher rate of CKM (HR=1.32 [95% CI, 1.20-1.45]) compared to day workers, after adjusting for sex, age, ethnicity, and socioeconomic factors. Elevated rates were also observed among those working 8 or more night shifts per month (HR=1.32 [95% CI, 1.21-1.43]) and those with over 1,200 lifetime night shifts (HR=1.36 [95% CI, 1.25-1.48]) as compared to day workers; all Ptrend<0.001. The association between night shift work and CKM risk was significantly modified by sleep duration, with higher rates among short sleepers (<7 hours/night;Pinteraction= 0.009, 0.031, and 0.017 for night shift work duration, intensity, and cumulative number of nights worked, respectively). However, chronotype did not significantly modify this association.Conclusion Our findings reveal a dose-response relationship between night shift work and CKM disease, which is further amplified by short sleep duration. Future studies should consider using CKM conditions as a composite outcome and investigate further how various sleep characteristics may modify the impact of night shift work.