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Background: Sex workers, like others, are facing economic hardships and anxiety about their health and safety due to coronavirus disease-2019 (COVID-19), an infectious disease caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Universally, most sex work has largely reduced, moved online, or undertaken covertly because of lockdown measures and need for social distancing to break the transmission of SARS-CoV-2. However, the ability of sex workers to protect themselves against COVID-19 depends on their individual and interpersonal behaviors and work environment. In this study, we sought to determine the relationships between COVID-19 knowledge, awareness and prevention practice (KAP) among female commercial sex workers (FCSW) in the Niger Delta region of Nigeria to inform the development of prevention interventions for this vulnerable population. Methods: Data used in this study were obtained from a cross-sectional survey of 604 FCSW operating in the Niger Delta region of Nigeria. We used descriptive and inferential statistics to assess their socio-demographic characteristics and COVID-19 KAP adopted against the novel coronavirus. Latent class analysis was used to systematically classify participants' attributes and behaviors into the most likely distinct clusters or risk groups. Results: The majority of the FCSW were singles (86.8%) of childbearing ages, 21– 35 years (86.2%), with almost three quarters (73.2%) of them having sex with 3– 4 clients per day during the COVID-19 pandemic. Overall, almost three quarters of the participants had both good knowledge and awareness about COVID-19 but less than half of them (41.1%) implemented good practice to prevent the spread of the disease. However, a highly significant and positive relationship was recorded between COVID-19 knowledge (r=0.90, p< 0.0001) and awareness (r=0.65, p< 0.0001), and preventive practice of FCSW, respectively. About 89.1% of the participants were not very familiar with the symptoms of COVID-19 (p< 0.0001). Only 10.9% of the FCSW indicated that they wear facemask at all times, while 45.2% of them do not wear facemask during sexual intercourse with their clients (p< 0.0001). Based on the FCSW attributes and behaviors, we identified three distinct clusters or risk groups (p< 0.0001), namely, low-risk takers (Cluster 1), high-risk takers (Cluster 2) and very high-risk takers (Cluster 3) with latent class prevalence rates (γc) of 41.13% (95% CI: 37.26– 45.10), 33.17% (95% CI: 29.53– 37.02) and 25.71% (95% CI: 22.38– 29.34), respectively. Conclusion: Sex work has high transmission potentials for SARS-CoV-2 because of its operational nature, which does not permit social distancing, and thus, renders certain preventive measures practically ineffective. This is a major challenge in the fight against COVID-19 in this high-risk group and calls for the development of operational guidelines and targeted intervention strategies to help reduce the spread of COVID-19 in the Niger Delta region. [ABSTRACT FROM AUTHOR]