Abstract Background Tuberous sclerosis complex lesions of the skin may be disfiguring to patients and can only be treated by laser or cosmetic surgery. Clarification of the molecular and structural changes involved in skin hamartomas may unravel targets for pharmacotherapy. Objective We investigated the expression of matrix metalloproteinase (MMP) and its tissue inhibitor (TIMP) in fibrous plaques, angiofibromas, and lesion-free skin specimens from patients with tuberous sclerosis complex. Methods Gene expression of MMPs and TIMP-1 was measured by reverse transcription polymerase chain reaction, gelatinase activity by gelatin zymography, and the content of collagenases and TIMPs by enzyme-linked immunosorbent assay. Results Compared with lesion-free specimens, hamartomas exhibited decreased levels of TIMPs and messenger RNA expression of TIMP-1, and increased content of MMP-1 and MMP-13 and activity of MMP-9, although gelatinase gene expression was diminished. Gene expression of MMP-15 and MMP-17 was not affected but was diminished for MMP-14. Conclusion The significant variations of the above extracellular matrix molecules between lesion-free specimens and tuberous sclerosis complex hamartomas overall favors a collagenous protein-degrading microenvironment in affected skin, and argue in support of antiprotease treatment for disfiguring skin lesions.