Our results highlight an important organ‐specific difference in PGE2‐mediated cAMP production in SSc MFs while demonstrating the common dedifferentiating effects of cAMP, the substantial effect of PDE4 activity on cAMP levels within SSc skin MFs, and the cAMP‐mediated inhibition of p38α within SSc fibroblasts from both organs. Here, PDE4A is linked to systemic sclerosis.