Advances in anesthesia and surgery enable children to receive anesthesia with relative safety. Recently, young age, prolonged, and multiple anesthetics have been highlighted as risk factors for poorer neurodevelopmental outcome, with neurotoxicity of anesthetic agents as a putative causal link. Because epidemiologic studies cannot fully disentangle patient factors associated with outcome, questions persist about causality, and neurodevelopmental attainment may be a health outcome with multiple genetic, social, and physiologic determinants. We hypothesized that the risk factors of age, multiple and prolonged exposure to anesthesia and surgery would be related to the hard outcome of mortality, not uniquely linked to neurodevelopment. Methods: Records from all patients having anesthesia or surgery at the Children’s Hospital of Wisconsin and its outpatient center from 2013-2016 were used in this analysis. Age, ASA-PS score, individual and cumulative anesthesia duration, number of case, and interval between date of service and death were extracted. Data were summarized by count (%) mean ± SD, median (IQR), and range. Relationships between risk factors and outcome were tested by likelihood ratio tests, logistic regression, and multiple regression techniques, with predicted risks expressed as point estimate ± SE or (5-95% CI). Analysis was performed using Stata (v14, Statacorp). Results: Data from 104237 cases in 61088 patients were analyzed, with average cases/patient 1.73±2.3, range 1-87. Patients were age 5.36(9.7) years, 19.6(30.4) kg, ASA-PS 2.26±0.84. Death occurred in 400 patients for a patient-mortality rate of 0.65% (CI 0.59-0.72). The overall risk of death by case was 0.135% (CI 0.114-0.160) at 48 hours, 0.539% (CI 0.49-0.59) at 30 days, and 2.62% (CI 2.52-2.72) at an average follow-up time of 800 days. Death occurred at a median of 147(320, range 0-1483) days after any case, at 172(465) days after the first case, and at 20(90) days after the last case (figure). Younger age, higher ASA-PS, case duration, and number of cases were mortality risk factors. ASA-PS was correlated with exposure to multiple and prolonged procedures. Mortality odds ratios were 1.80 (CI 1.67-1.95) for age<3 years, 16.2 (CI 14.9-17.6) for ASA>3, 2.09 (CI 1.88-2.31) for anesthesia duration>3hours, 19.1 (CI 16.6-22.0) for number of cases>3, and 9.96 (CI 9.00-11.0) for cumulative anesthesia duration>3hours. The combination of age<3yrs and case duration>3hrs identified 3234 (3.14%) cases, with average ASA 3.21±0.87, and mortality odds of 3.36 (CI 2.94-3.85). In multiple regression analysis (table), greater cumulative case time and multiple cases remained risk factors, while longer duration for each individual case was not. The cutoff age for higher risk was <2 years. Conclusions: Mortality following anesthesia and surgery is highly related to patient characteristics including younger age and higher ASA-PS. While both multiple and prolonged exposures are associated with increased mortality, these risks are small in multifactorial analysis. These results suggest that young age, prolonged and multiple exposures are relatively small and unmodifiable proxy measures of patient factors related to outcome.