Tuberous sclerosis complex (TSC) is a rare disease that threatens multiple organs in the human body. TSC-associated renal angiomyolipoma (TSC-RAML) has potentially life-threatening complications and a generally poor prognosis. The present study aimed to find plasma proteomic diagnostics and disease-associated markers, and explore the tumor microenvironment using multi-omics. To achieve this goal, the plasma proteomics as well as tissue proteomics, bulk and single-cell RNA transcriptome from patients with TSC-RAML were examined and analyzed. The results suggested that plasma proteins such as MMP9 and C-C motif chemokine ligand 5 were able to differentiate TSC-RAML from sporadic angiomyolipoma and renal cyst. A correlation analysis revealed that plasma proteomics were associated with lymphangioleiomyomatosis, TSC-RAML grading and whole-body disease burden. Tissue proteomics of participants with TSC-RAML revealed disturbed small molecule catabolic process, mitochondrial matrix component and actin binding function. Bulk and single-cell RNA sequencing suggested a greater number of tumor-like cells, fibroblasts and mono- nuclear macrophages within the tumor microenvironment. The above results indicated that TSC-RAML exhibited a characteristic and disease-associated plasma proteomic profile. The unique microenvironment, made up of fibroblasts and mono-macrophages, may promote tumorigenesis and TSC-RAML progression. © 2022 Spandidos Publications. All rights reserved.