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Acrochordons are prevalent in the general population and may signify insulin resistance. Multiple acrochordons on the neck, known as the necklace sign, have been observed in tuberous sclerosis complex (TSC), a genetic disorder characterized by tumors in multiple organs. Tumorigenesis in TSC involves activation of mechanistic target of rapamycin (mTOR) signaling with concomitant disruption of insulin sensitivity. We sought to determine if the necklace sign is associated with increased phenotypic severity of TSC, reasoning that presence of acrochordons in some individuals may indicate heightened susceptibility to mTOR activation. We performed a retrospective chart review of a cohort of 113 adult women with TSC enrolled for studies of pulmonary lymphangioleiomyomatosis (LAM), a female-predominant manifestation of TSC. Twenty-four patients were excluded due to inadequate photos and 7 due to segmental disease. Of the 82 patients analyzed, 20 (24.3%) showed the necklace sign, defined as 2 or more acrochordons on the neck. The frequency of LAM was greater in patients with the necklace sign (20/20, 100%) compared to those without (48/62, 77.4%) (p¼0.017). LAM symptom onset age was earlier in patients with the necklace sign (30.3 years, n¼19) than those without (35.6 years, n¼43) (p¼0.023). In patients with the necklace sign, pulmonary function measured by % predicted forced expiratory volume in 1 second (80.5, n¼20) and % predicted diffusing capacity for carbon monoxide (85.6, n¼20) were lower compared to those without (89.7, n¼48 (p¼0.12); 69.3, n¼48 (p¼0.010), respectively). Initial cyst burden, determined computationally using chest CT scans, was higher in patients with the necklace sign (13.2%, n¼16) versus those without (7.21%, n¼43) (p¼0.044). These results suggest that the necklace sign may aid in identification of TSC patients at risk for developing more severe LAM earlier in life and that interindividual variability in mTOR signaling may influence TSC-associated tumorigenesis.