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Refugees and migrants remain one of the most vulnerable people and the COVID-19 pandemic has posed additional challenges both in terms of increased risk of infection and death experienced, highlighting existing inequities in access to and utilization of health services, as underlined by World Health Organization in 2020 in the Health and Migration Programme. In the context of the Programme 'Epidemiological surveillance and control of COVID-19 in metropolitan urban areas and for the containment of the circulation of SARS-CoV-2 in the migrant population in Italy', coordinated by the Italian Centre for Disease Control and Prevention (CCM) and funded by the Italian Ministry of Health, an experimental epidemiological, virological, and molecular SARS-CoV-2 surveillance system addressed to migrant populations in Sicily through Mediterranean routes was implemented. To this end, a multidisciplinary network supported by a hub&spoke system of laboratories was established in Sicily Region (Southern Italy), using molecular and Next Generation Sequencing (NGS) techniques to identify different SARS-CoV-2 strains in relation to migration flows. Herein, the lesson learnt through this integrated surveillance model, that was in place from February 2021 till the end of the COVID-19 emergency in Italy, are reported. Overall, the data emphasized the need for enhancing molecular surveillance in the areas of the globe where testing and sequencing resources are limited. The epidemiological, virological, and molecular SARS-CoV-2 monitoring, targeted to the migrant population, may also provide a valuable experimental model.