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Abstract Advanced glycation end products (AGEs) dysregulate adipokines and induce inflammation by binding to their adipocyte receptor (RAGE). Soluble RAGE (sRAGE) prevents AGEs/RAGE signaling. We performed a nested case–control study of the association between sRAGE, adipokines, and incident pancreatic cancer risk in the prospective Women's Health Initiative Study. We individually matched controls (n = 802) to cases (n = 472) on age, race, and blood draw date. We evaluated serum concentrations of sRAGE, adiponectin, leptin, monocyte chemotactic protein 1 (MCP1), and plasminogen activator inhibitor‐1 (PAI1) using immunoassay. We used conditional logistic regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for pancreatic cancer over biomarker quartiles (Q1–Q4). We used principal component analysis to create two composite biomarkers and performed a confirmatory factor analysis to examine the association between composite biomarker scores (CBS) and pancreatic cancer risk. Baseline serum sRAGE concentrations were inversely associated with pancreatic cancer risk (aORQ4 vs. Q1 = 0.70, 95% CI: 0.50–0.99). High MCP1 (aOR Q4 vs. Q1 = 2.55, 95% CI: 1.41–4.61) and the higher CBS including MCP1, PAI1, and leptin (aORQ4 vs. Q1 = 1.82, 95% CI = 1.04–3.18) were also associated with increased pancreatic cancer risk among women with BMI <25 kg/m2 (P values for interaction <0.05). We found an inverse association between prediagnostic sRAGE concentrations and risk of incident pancreatic cancer in postmenopausal women. A proinflammatory CBS was associated with increased risk only in women with normal BMI. MCP1 was not modulated by sRAGE.