Background In order to promote the health of nurses while maintaining performance and patient care safety standards, better research bases on the association of work organization with health are needed. Methods Work schedule components (shift, shift length, weekends, and overtime) in a nationally representative sample of employed registered nurses participating in an anonymous mailed survey (n Ο 3,917) were examined in relation to past year alcohol, smoking and drug use. Results Schedule components examined separately showed modest associations with substance use. Combinations of shift and shift length interacted in association with substance use, so that nurses working night shifts ΟΎ8 hr had the highest likelihood of alcohol use and smoking and those working rotating shifts ΟΎ8 hr were more likely to report alcohol use. Among women, the likelihood of substance use under adverse conditions varied by family/home demands. Conclusions Administrative attention to the interplay of work schedules on workers along with consideration of competing family/home demands could lead to more healthful scheduling. In addition to substance use, working longer night and rotating shifts might be related to other health behaviors and conditions that should be examined in the future. Am.