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Nondepolarizing neuromuscular blocking drugs (NNMBDs) are commonly used as an adjunct to general anesthesia. Residual blockade is common, but its potential adverse effects are incompletely known. This study was designed to assess the association between NNMBD use with or without neostigmine reversal and postoperative morbidity and mortality.This is a retrospective observational study of 11,355 adult patients undergoing general anesthesia for noncardiac surgery at 5 Veterans Health Administration (VA) hospitals. Of those, 8984 received NNMBDs, and 7047 received reversal with neostigmine. The primary outcome was a composite of respiratory complications (failure to wean from the ventilator, reintubation, or pneumonia), which was “yes” if a patient had any of the 3 component events and “no” if they had none. Secondary outcomes were nonrespiratory complications, 30-day and long-term all-cause mortality. We adjusted for differences in patient risk using propensity matched (PM) followed by assessment of the association of interest by logistic regression between the matched pairs as our primary analysis and multivariable logistic regression (MLR) as a sensitivity analysis.Our primary aim was to assess the adverse outcomes in the patients who had received NNMBDs with and without neostigmine. Administration of an NNMBD without neostigmine reversal compared with NNMBD with neostigmine reversal was associated with increased odds of respiratory complications (PM odds ratio [OR], 1.75 [95% confidence interval [CI], 1.23–2.50]; MLR OR, 1.71 [CI, 1.24–2.37]) and a marginal increase in 30-day mortality (PM OR, 1.83 [CI, 0.99–3.37]; MLR OR, 1.78 [CI, 1.02–3.13]). However, there were no statistically significant associations with nonrespiratory complications or long-term mortality. Patients who were administered an NNMBD followed by neostigmine had no differences in outcomes compared with patients who had general anesthesia without an NNMBD.The use of NNMBDs without neostigmine reversal was associated with increased odds of our composite respiratory outcome compared with patients reversed with neostigmine. Based on these data, we conclude that reversal of NNMBDs should become a standard practice if extubation is planned.