BACKGROUND: Survival after in-hospital cardiac arrest (IHCA) is lower during nights and weekends (off-hours) compared with daytime during weekdays (on-hours). As overall IHCA survival has improved over time, it remains unknown whether survival differences between on-hours and off-hours have changed. OBJECTIVES: This study sought to examine temporal trends in survival differences between on-hours and off-hours IHCA. METHODS: We identified 151,071 adults at 470 U.S. hospitals in the Get with the Guidelines-Resuscitation registry during 2000 to 2014. Using multivariable logistic regression with generalized estimating equations, we examined whether survival trends in IHCA differed during on-hours (Monday to Friday 7:00 am to 10:59 pm) versus off-hours (Monday to Friday 11:00 pm to 6:59 am, and Saturday to Sunday, all day). RESULTS: Among 151,071 participants, 79,091 (52.4%) had an IHCA during off-hours. Risk-adjusted survival improved over time in both groups (on-hours: 16.0% in 2000, 25.2% in 2014; off-hours: 11.9% in 2000, 21.9% in 2014; p for trend <0.001 for both). However, there was no significant change in the survival difference over time between on-hours and off-hours, either on an absolute (p = 0.75) or a relative scale (p = 0.059). Acute resuscitation survival improved significantly in both groups (on-hours: 56.1% in 2000, 71% in 2014; off-hours: 46.9% in 2000, 68.2% in 2014; p for trend <0.001 for both) and the difference between on-hours and off-hours narrowed over time (p = 0.02 absolute scale, p < 0.001 relative scale). In contrast, although post-resuscitation survival also improved over time in both groups (p for trend < 0.001 for both), the absolute and relative difference persisted. CONCLUSIONS: Despite an overall improvement in survival, lower survival in IHCA during off-hours compared with on-hours persists.