Introduction <p>Sickle cell disease (SCD) is characterized by vaso-occlusive crises (VOCs) that can lead to clinical complications, higher mortality, and healthcare resource use (HCRU). Lack of Canadian data poses challenges to health system planning, a gap this study intends to close. We analyzed clinical complications, mortality, and HCRU in patients with SCD with recurrent VOCs in Canada.</p> Methods <p>This retrospective cohort study identified patients with SCD with recurrent VOCs from the Institute for Clinical Evaluative Sciences (ICES) databases in Ontario, Canada from January 1, 2010, to December 31, 2021. VOCs were defined as SCD with crisis, priapism, or acute chest syndrome. Patients were matched (1:3) by age, sex, and geographic area with non-SCD individuals in the general population. Clinical complications, mortality, and HCRU were analyzed.</p> Results <p>Eight hundred fifty-nine patients with SCD with recurrent VOCs were identified and matched to 2577 controls. Mean (standard deviation [SD]) age was 22.1 (14.4) years; 50.9% were female. Mean (SD) rate of VOCs per person per year was 3.2 (4.4) in patients with recurrent VOCs. Acute and chronic complication rates were higher in patients than controls. Compared with controls, mortality was substantially higher for patients with recurrent VOCs. Mean (SD) age at death for patients with recurrent VOCs was 39.2 (17.2) years. There was significantly higher HCRU than matched controls (<i>P</i> &lt; 0.0001).</p> Conclusion <p>Patients with SCD with recurrent VOCs had substantially higher rates of complications, mortality, and HCRU than controls, further highlighting the need for novel therapies to reduce VOCs and the associated burden.</p>