The cause of scleroderma is still unknown. Scientists are working diligently to understand what biological factors contribute to scleroderma pathogenesis.

Genetic Factors: Association of SSc with HLA class II alleles HLA-DR, DQ, DP exists.

Environmental Factors: Chemical like silica, heavy metals like mercury, organic chemicals vinyl chloride, benzene, toluene, trichloroethylene; drugs (bleomycin, pentazocin, taxol, cocaine; appetite suppressants like L tryptophan, mazindol, fenfluramine, diethylpropion) have been implicated.

Infectious agents: Cytomegalovirus and Epstein Barr virus probably play a role due to molecular mimicry.