Stand-alone portable air purifiers (APs) have become an increasingly popular method of controlling individual inhalation exposure. Exposure to bacterial endotoxins has a causative role in respiratory inhalation health. Here, we studied the changes in endotoxin levels in indoor air before and after purification by a portable AP equipped with HEPA (high-efficiency particulate air) filters. An increase in endotoxins was observed when a previously used AP was turned on to clean the air. Replacing the HEPA filters in the AP helped to mitigate the increase in endotoxins of larger sizes but not endotoxins of smaller sizes. Consequently, the use of APs could lead to increased endotoxin deposition in airways, especially in the alveolar region. The endotoxin concentrations on the HEPA filters were well correlated with the free DNA concentrations on the HEPA filters. This correlation indicates that the disrupted bacteria, which released free DNA, could also release endotoxins, thus making HEPA filters a source of indoor airborne endotoxins. Our results illustrate a potential endotoxin inhalation risk associated with HEPA-APs as an air cleaning strategy and highlight the importance of composition-specific air cleaning while reducing the particle number/mass.