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• The early COVID-19 epidemic in South Africa was highly heterogeneous looking at the epidemiological progression between major provinces. • Early transmission in KwaZulu-Natal (KZN) was associated with multiple international introductions of SARS-CoV-2. • The dominating lineages during this time of the epidemic were B.1 and B, which mainly originated from Europe. • Evidence for transmission clusters during the first month of the epidemic suggested locally acquired infection. • A clustered outbreak was linked to a major hospital outbreak in Durban, which inflated the early mortality in KZN. The Network for Genomic Surveillance in South Africa (NGS-SA) was formed to investigate the introduction and understand the early transmission dynamics of the SARS-CoV-2 epidemic in South-Africa. This paper presents the first results from this group, which is a molecular epidemiological study of the first 21 SARS-CoV-2 whole genomes sampled in the first port of entry – KwaZulu-Natal (KZN) – during the first month of the epidemic. By combining this with calculations of the effective reproduction number (R), it aimed to shed light on the patterns of infections in South Africa. Two of the largest provinces – Gauteng and KZN – had a slow growth rate for the number of detected cases, while the epidemic spread faster in the Western Cape and Eastern Cape. The estimates of transmission potential suggested a decrease towards R = 1 since the first cases and deaths, but a subsequent estimated R average of 1.39 between 6–18 May 2020. It was also demonstrated that early transmission in KZN was associated with multiple international introductions and dominated by lineages B1 and B. Evidence for locally acquired infections in a hospital in Durban within the first month of the epidemic was also provided. The COVID-19 pandemic in South Africa was very heterogeneous in its spatial dimension, with many distinct introductions of SARS-CoV2 in KZN and evidence of nosocomial transmission, which inflated early mortality in KZN. The epidemic at the local level was still developing and NGS-SA aimed to clarify the dynamics in South Africa and devise the most effective measures as the outbreak evolved. [ABSTRACT FROM AUTHOR]