Purpose Frequent Emergency Department users are likely to experience poor quality of life (QOL). Case management interventions are efficient in responding to the complex needs of this population, but their effects on QOL have not been tested yet. Therefore, the aim of our study was to examine to what extent a case management intervention improved frequent Emergency Department users’ QOL in a universal health coverage system. Methods Data were part of a randomized controlled trial designed to improve frequent Emergency Department users’ QOL at the Lausanne University Hospital, Switzerland. A total of 250 frequent Emergency Department users (≥ 5 attendances during the previous 12 months) were randomly assigned to the control (n = 125) or the intervention group (n = 125). The latter benefited from case management intervention. QOL was evaluated using the WHOQOL-BREF at baseline, two, five and a half, nine, and twelve months later. It included four dimensions: physical health, psychological health, social relationship, and environment. Linear mixed-effects models were used to analyze the change in the patients’ QOL over time. Results Patients’ QOL improved significantly (p < 0.001) in both groups for all dimensions after two months. However, environment QOL dimension improved significantly more in the intervention group after 12 months. Conclusions Environment QOL dimension was the most responsive dimension for short-term interventions. This may have been due to case management’s assistance in obtaining income entitlements, health insurance coverage, stable housing, or finding general health care practitioners. Case management in general should be developed to enhance frequent users’ QOL. Trial registration:, Unique identifier: NCT01934322