PURPOSE: Obesity is associated with poor lymphatic solute drainage. It is unclear whether the chronic inflammation, hypoxia, and hyperlipidemia that are together associated with obesity cause impaired drainage function, and if so, whether these conditions act directly on lymphatic endothelial cells (LECs) or are indirectly mediated by the mechanical properties or cellular composition of the surrounding tissue. METHODS: We engineered blind-ended lymphatic vessels in type I collagen gels and simulated the obese microenvironment with a cocktail of tumor necrosis factor (TNF)-α, cobalt chloride (CoCl RESULTS: Lymphatics that were exposed to simulated obesity exhibited more gaps in endothelial junctions, leaked more solute, and drained solute less quickly than control lymphatics did, regardless of matrix stiffness. CM from adipose cells that were exposed to simulated obesity did not affect lymphatics. Lymphatics in adipocyte-laden gels did not exhibit worse drainage function when exposed to simulated obesity. CONCLUSIONS: The combination of obesity-associated inflammation, hypoxia, and hyperlipidemia impairs lymphatic solute drainage and does so by acting directly on LECs. Surprisingly, adipocytes may play a protective role in preventing obesity-associated conditions from impairing lymphatic solute drainage. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-024-00840-z.