Abstract Background: A correlation between prior exposure to Mycoplasma pneumoniae (IgG positive) and better clinical response to COVID-19 was elusive. Methods: A retrospective review of all COVID-19 infected patients treated at Wuhan Union Hospital from Feb 1 to Mar 20 was carried out. Continuous variables were described as mean, median, and interquartile range (IQR), while categorical variables were compared by X2 test or Fisher's exact test between COVID-19 infected patients with mycoplasma lgG (-) and mycoplasma lgG (+). Results: Statistically significant differences were shown in terms of laboratory test results. COVID-19 infected patients with mycoplasma lgG positivity had a higher lymphocyte count and percentage (p=0.026, p=0.017), monocyte count and percentage (p=0.028, p=0.006) and eosinophil count and percentage (p=0.039, p=0.007), and a lower neutrophil count and percentage (p=0.044, p=0.006) than COVID-19 infected patients without mycoplasma lgG. Other routine blood tests, including coagulation tests, blood biochemistry and infection-related biomarkers did not significantly differ except for thrombin time (p=0.001) and lactate dehydrogenase (p=0.008). Furthermore, requirement and use of a nasal catheter or oxygen mask was significantly lower in COVID-19 infected patients with mycoplasma lgG positivity (p=0.029). Conclusions: Our findings indicate that mycoplasma IgG positivity is a potential protective factor for SARS-CoV-2 infection.