OBJECTIVE To investigate the associations between different anthropometric measurements and development of distal sensorimotor polyneuropathy (DSPN) considering interaction effects with prediabetes/diabetes and to evaluate subclinical inflammation as a potential mediator. RESEARCH DESIGN AND METHODS This study was conducted among 513 participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (aged 62–81 years). Anthropometry was measured at baseline. Incident DSPN was defined by neuropathic impairments using the Michigan Neuropathy Screening Instrument at baseline and follow-up. Associations between anthropometric measurements and DSPN were estimated by multivariable logistic regression. Potential differences by diabetes status were assessed using interaction terms. Mediation analysis was conducted to determine the mediation effect of subclinical inflammation in these associations. RESULTS After a mean follow-up of 6.5 years, 127 cases with incident DSPN were detected. Both general and abdominal obesity were associated with development of DSPN. The odds ratios (95% CI) of DSPN were 3.06 (1.57; 5.97) for overweight, 3.47 (1.72; 7.00) for obesity (reference: normal BMI), and 1.22 (1.07; 1.38) for 5-cm differences in waist circumference, respectively. Interaction analyses did not indicate any differences by diabetes status. Two chemokines (C-C motif chemokine ligand 7 [CCL7] and C-X-C motif chemokine ligand 10 [CXCL10]) and one neuron-specific marker (Delta/Notch-like epidermal growth factor–related receptor [DNER]) were identified as potential mediators, which explained a proportion of the total effect up to 11% per biomarker. CONCLUSIONS General and abdominal obesity were associated with incident DSPN among individuals with and without diabetes, and this association was partly mediated by inflammatory markers. However, further mechanisms and biomarkers should be investigated as additional mediators to explain the remainder of this association.