In a previous study in Belgian nursing homes (NH) during the first wave of the COVID-19 pandemic, we found a SARS-CoV-2 seroprevalence of 17% with a large variability (0–45%) between NH. The current exploratory study aimed to identify nursing home-specific risk factors for high SARS-CoV-2 seroprevalence. Between October 19^th, 2020 and November 13^th, 2020, during the second COVID-19 wave in Belgium, capillary blood was collected on dried blood spots from 60 residents and staff in each of the 20 participating NH in Flanders and Brussels. The presence of SARS-CoV-2-specific IgG antibodies was assessed by ELISA. Risk factors were evaluated using a questionnaire, filled in by the director or manager of the NH. Assessed risk factors comprised community-related factors, resident-related factors, management and performance features as well as building-related aspects. The relation between risk factors and seroprevalence was assessed by applying random forest modelling, generalized linear models and Bayesian linear regression. The present analyses showed that the prevalence of residents with dementia, the scarcity of personal protective equipment (surgical masks, FFP2 masks, glasses and face shields), and inadequate PCR test capacity were related to a higher seroprevalence. Generally, our study put forward that the various aspects of infection prevention in NH require more attention and investment. This exploratory study suggests that the ratio of residents with dementia, the availability of test capacity and personal protective equipment may have played a role in the SARS-CoV-2 seroprevalence of NH, after the first wave. It underscores the importance of the availability of PPE and education in infection prevention. Moreover, investments may also yield benefits in the prevention of other respiratory infections (such as influenza).