Study objective Emergency department (ED) crowding is a common and complicated problem challenging EDs worldwide. Nurse-initiated protocols, diagnostics, or treatments implemented by nurses before patients are treated by a physician or nurse practitioner have been suggested as a potential strategy to improve patient flow. Methods This is a computer-randomized, pragmatic, controlled evaluation of 6 nurse-initiated protocols in a busy, crowded, inner-city ED. The primary outcomes included time to diagnostic test, time to treatment, time to consultation, or ED length of stay. Results Protocols decreased the median time to acetaminophen for patients presenting with pain or fever by 186 minutes (95% confidence interval CI 76 to 296 minutes) and the median time to troponin for patients presenting with suspected ischemic chest pain by 79 minutes (95% CI 21 to 179 minutes). Median ED length of stay was reduced by 224 minutes (95% CI –19 to 467 minutes) by implementing a suspected fractured hip protocol. A vaginal bleeding during pregnancy protocol reduced median ED length of stay by 232 minutes (95% CI 26 to 438 minutes). Conclusion Targeting specific patient groups with carefully written protocols can result in improved time to test or medication and, in some cases, reduce ED length of stay. A cooperative and collaborative interdisciplinary group is essential to success.