The aims of this study were to 1) estimate differences in pain management process and patient-reported outcomes, pre- and postimplementation of analgesic protocols for adults with sickle cell disease (SCD), and 2) examine the effects of site and visit frequency on changes in pain scores and time to analgesic. A multicenter, prospective, longitudinal study enrolled patients from three academic medical centers between October 2007 and September 2009. All ED patients 18 years or older with a chief complaint of a sickle cell pain episode were enrolled. Sites formed a SCD quality improvement (QI) team and implemented standard nurse-initiated emergency department (ED) analgesic protocols; outcomes were compared between study periods defined as pre- and postimplementation of protocols. Medical record review was conducted to measure time to administration of initial analgesic, opioids used, route of opioid administration, the change in pain scores from arrival to discharge (negative numbers reflect a decrease in pain scores), and the number of ED visits per individual patient during the study period at each site. On day 7 after the ED visit, a follow-up phone interview was conducted. Patients were queried about their ED pain management using a scale from 1 to 10 (1 = outstanding, 10 = worst). Descriptive statistics are used to report the results. Ordinary least-squares regression models were constructed to measure the effect of time period, site, and number of visits per patient on change in pain score. During the study period, 342 unique patients (57% female, mean ± SD age = 32 ± 11 years) were enrolled and had a total of 2,934 visits. There was no difference in time to administration of the initial analgesic between study periods. Overall, there was a significant decrease in pain scores from arrival to discharge between the pre- and postintervention study periods: the average difference in arrival to discharge pain scores (cm) was greater during the postimplementation period than during the preintervention period (-4.1 vs. -3.6, t = 2.6, p < 0.01). Site 1 had significant improvement between study periods (mean difference = -0.87, t = 2.63, p < 0.01; F = 14.3, p < 0.01). Patients with few ED visits (one to six annual visits, mean difference = -1.55, t = 2.1, p = 0.04) and those with frequent ED visits (7 to 19 annual visits, mean difference = -1.65, t = 3.52, p < 0.01) had a significant decrease in pain scores compared to patients with very frequent ED visits (>19 visits). There was an overall decrease in the use of morphine sulfate (MS) and increase in the use of hydromorphone (χ(2) = 105.67, p < 0.001) between study periods and a significant increase in the use of oral (PO) and subcutaneous (SC) routes, with a corresponding decrease in the intravenous (IV) route (χ(2) = 13.67, p < 0.001). There were no statistically significant differences in patient-reported satisfaction with the attempt to manage pain in the ED between study periods (p = 0.54). While the use of a learning collaborative and implementation of nurse-initiated analgesic protocols was not associated with improvement in time to administration of the initial analgesic, improvements in the decrease in the arrival to discharge pain score and increased use of hydromorphone and the SC route were noted in adults with SCD in the ED.