Introduction: Approximately 20% of Canadians who present to emergency departments (EDs) with acute asthma relapse within 4 weeks of discharge. The reasons are likely multi-factorial; however, the lack of timely primary care provider (PCP) follow-up and inadequate patient self-management are thought to be important variables. Therefore, we tested the effectiveness of ED-directed multifaceted interventions that targeted PCPs and enhanced patient self-management to reduce asthma relapse following ED discharge. Methods: Adults with acute asthma discharged from 6 Alberta EDs were randomly allocated, in a centralized and concealed manner, to receive usual care (UC), opinion leader [OL] guidance to their PCPs, or OL guidance + nurse case-management [OL+CM] for patients (NCT01079000). The main outcome was asthma relapse within 90-days of ED discharge. Secondary outcomes included PCP visits, time to relapse, hospitalizations and asthma-related quality of life (QoL). Outcomes were collected independently and assessors were masked to intervention assignment. Results: From 943 screened patients, 367 patients were allocated to the study arms (UC=146; OL=110; OL+CM=111). Median age was 28 years, 64% were women, median peak flow at discharge was 350 L/min; 77% were discharged home on prednisone and 85% on either inhaled corticosteroids (ICS) or ICS/long-acting β2-agonists. Compared with UC, both interventions significantly increased rates of relapse at 90-days: UC=12%, OL=28%, OL+CM=19%; p=0.006. Based on an absolute increased risk of 0.16 (95% CI: 0.05, 0.25), the number needed to treat for harm was 6 (95% CI: 3.9, 19.0) for the OL arm. Across study differences in PCP follow-up visits, time to relapse, hospitalizations or asthma-related QoL were not identified. Conclusion: Two different theory-informed and evidenced-based interventions intended to decrease asthma relapse robustly and significantly increased rates of relapse compared with UC. While the reasons for these unintended consequences require further study, we caution against the adoption of similar interventions by other EDs.