Several mutations and atypical splice variants of WISP3 (CCN6) have been linked to connective tissue disorders and different forms of malignancies. Functional studies have suggested that WISP3 contributes to tissue maintenance/homeostasis. The precise molecular mechanism of WISP3 function in different cell types, however, remains unresolved. The present study was conducted to investigate the potential impact of WISP3 on the accumulation of reactive oxygen species (ROS) and oxidative stress, which are central to cell/tissue maintenance. Our experimental results suggest that WISP3 regulates the accumulation of cellular ROS, and mutations in WISP3 or loss of expression of WISP3 compromise this function.