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Greece opened its points of entry on July 1, 2020, with specific guidelines for travellers arriving by sea, air or land. The aim of this article is to examine the effect of tourism on the long term course of the Coronavirus Disease 2019 (COVID-19) pandemic during the pre-vaccination era (June to December 2020) on the popular Greek island of Crete. To achieve this, a cross-sectional serosurvey, repeated at monthly intervals, was conducted to compare the seroprevalence in Crete with seroprevalence in the mainland of Greece. Crete welcomed nearly 2,000,000 travellers during the 2020 summer season. Left-over serum samples were collected and obtained from public and private laboratories located in Greece, including the island of Crete. These samples were tested for the presence of anti-SARS-CoV-2 IgG antibodies. A total of 55,938 samples were collected, 3,785 of which originated from Crete. In Crete, the seroprevalence ranged between 0% (June 2020) and 2.58% (December 2020), while the corresponding seroprevalence in Greece was 0.19% and 10.75%, respectively. We identified 4.16 times lower seropositivity in Crete (2.58%) in comparison with the mainland of Greece (10.75%) during December 2020. Moreover, the monthly infection fatality rate (IFR) in Crete was calculated at 0.09%, compared with 0.21% in mainland Greece for December 2020. The island of Crete presented more than four times lower seroprevalence than the mainland of Greece, despite being a highly attractive tourist destination. This evidence supports the idea that tourism may not have affected the long term course of the COVID-19 pandemic in Greece. However, due to contradicting results from previous studies, further investigation is needed.