Background Patients admitted to hospital outside normal working hours suffer higher complication and mortality rates than patients admitted at times when the hospital is fully operational. This ‘weekend effect’ is well described but poorly understood. It is not clear whether or not the effect extends to other out-of-hours periods, or how far excess mortality for out-of-hours admissions reflects a different presenting population with higher severity of illness and how much is explained by poorer availability and quality of services. Objectives We aimed to assess (1) the costs and benefits of introducing 7-day services, (2) whether or not mortality rates are elevated during all out-of-hours periods, (3) whether or not selection of more severely ill patients for admission out of hours explains elevated mortality rates and (4) whether or not mortality rates out of hours are related to staffing levels. Methods We conducted a series of retrospective observational analyses of hospital episode data in England, using both national data and data from a single, large acute NHS trust. For the national studies, we analysed emergency admissions to all 140 non-specialist acute hospital trusts in England between April 2013 and February 2014 (over 12 million accident and emergency attendances and 4.5 million emergency admissions). For the single trust, we analysed emergency admissions between April 2004 and March 2014 (240,000 admissions). Deaths within 30 days of attendance or admission were compared for normal working hours and out-of-hours periods. Results We found that, in addition to elevated mortality for weekend admissions, mortality rates are also elevated for patients admitted during night-time periods. Elevated mortality was reduced for stroke patients in a large acute trust when more – and more experienced – nursing staff were present during the first hour of admission. Nationally, we found that excess mortality out of hours was largely explained by a sicker population of patients being selected for admission. However, mortality rates were still elevated on Sunday daytimes when we accounted for severity of patient illness. We also found that the estimated cost of implementing 7-day services exceeds the maximum amount that the National Institute for Health and Care Excellence would recommend the NHS should spend on eradicating excess mortality at weekends. Limitations Our results depend on the accuracy and completeness of data recording by hospital staff. If accuracy of recording is related to time of patient admission, our results may be biased. Results based on data from a single trust should be treated as indicative. Conclusions In addressing variations in patient outcomes across the week, a more nuanced approach, extending services for key specialties over critical periods – rather than implementing whole-system changes – is likely to be the most cost-effective. Future work Future research should aim to develop and use appropriate measures of severity of illness to facilitate meaningful analysis of variations in patient outcomes, and to identify candidate specialties and critical periods for which extending services is likely to be cost-effective. Funding The National Institute for Health Research Health Services and Delivery Research programme.