Background Lipodystrophy is a group of heterogeneous syndromes characterized by selective loss of adipose tissue and metabolic abnormalities. The severity of pain and its possible relation to measures of quality of life (OoL) and psychoemotional and metabolic health have never been studied in-depth previously. Methods LD-Lync study is an international multi-center study collecting data on the natural history of different lipodystrophy syndromes. We have completed phase 1 of the study where only a single site (University of Michigan) entered data (n = 79 patients, M/F: 16/63, mean age: 46.13 ± 14.60, 56 with familial partial lipodystrophy). In this study, we sought to investigate the relationship of pain perception on QoL, psychoemotional and metabolic aspects of the disease. Brief Pain Inventory (BPI) was used to calculate pain severity (BPI-SS) and pain interference scores (BPI-IS). Results From the 77 who completed the questionnaires, 56 (72.73%) patients reported pain at different levels. Out of the 56, 29 (51.79%) patients had moderate/severe pain (BPI-SS ≥ 4). Patients with moderate/severe pain had “more impaired” QoL scores: physical functioning: 20 (15-50) vs. 80 (45-95), p = 0.002; limitation to physical health: 0 (0-25) vs. 75 (0-100), p = 0.002; energy/fatigue 15 (10-30) vs. 45 (20-60), p = 0.032; emotional well-being: 48 (32-60) vs. 72 (48-84), p = 0.029; social functioning: 33 (20-38) vs. 58 (35-70), p = 0.002; general health: 15 (10-25) vs. 35 (20-55), p = 0.005). Severe depression (PHQ-9 > 14) was more frequently detected among patients with moderate/severe pain (63.2% vs. 36.9%, p = 0.008). PHQ-9 score measuring depression was positively correlated with BPI-SS (r = 0.53, p < 0.001), and BPI-IS (r = 0.63, p < 0.001). Emotional burden score was also higher in patients reporting moderate/severe pain (4.0 (2.6-5.0) vs. 2.7 (1.6-3.3), p = 0.015). BPI-SS/BPI-IS scores correlated positively with disease distress (r = 0.33, p < 0.001, and r = 0.31, p = 0.010) and GAD7 scores measuring anxiety (r = 0.52, p < 0.001, and r = 0.50, p < 0.001). Anxiety (GAD7 > 10) was more prevalent among patients with moderate/severe pain (58.6% vs. 23.4%, p = 0.002). The presence of diabetes was associated with higher BPI-SS scores: 3.50 (1.50-5.00) vs. 0 (0-3.25), p = 0.030). Also, patients with HbA1c > 6.5% exhibited higher BPI-SS scores than those with an HbA1c less than 6.5%: 3.38 (1.38-5.00) vs. 1.25 (0-3.50), p = 0.030). Conclusion Our study reveals a high frequency of pain perception among patients with different types of lipodystrophy. Pain severity contributes to worsening in QoL, affects physical and emotional function, and relates to psychoemotional state in patients with lipodystrophy. In addition, the presence of diabetes and higher HbA1c may potentially modulate pain in patients with lipodystrophy. Further work is needed to elucidate the pathways that regulate pain in these patients and to address it effectively.