Aims: Emerging evidence has demonstrated that saturated fatty acids (SFA) prime pro-IL-1β production and inflammasome-mediated IL-1β activation is critical in obesity-associated insulin resistance (IR). Nonetheless, IL-1 receptor I deficient (IL-1RI^-/-) mice develop mature-onset obesity despite consuming a low-fat diet (LFD). With this apparent contradiction, the present study evaluated whether IL-1RI^-/- mice were protected against long-term (6 months (6mo)) HFD-induced IR. Methods: Male wild-Type (WT) and IL-1RI^-/- mice were fed LFD or HFD for 3 months (3mo) or 6mo and glucose (GTT) and insulin (ITT) tolerance tests performed. Adipose insulin sensitivity, cytokine profiles and adipocyte morphology were assessed. The adipogenic potential of stromal vascular fraction (SVF) was determined. Hepatic lipid accumulation and insulin sensitivity were characterized. Results: IL-1RI^-/- mice developed glucose intolerance and IR after 6mo HFD compared to 3mo HFD, coincident with enhanced weight-gain, hyperinsulinemia and hyperleptinemia. The aggravated IR phenotype was associated with loss of adipose functionality, switch from adipocyte hyperplasia to hypertrophy and hepatosteatosis. Induction of adipogenic genes was reduced in IL-1RI^-/- pre-adipocytes after 6mo HFD compared to 3mo HFD. Obese LFD-IL-1RI^-/- mice exhibited preserved metabolic health. Conclusions: IL-1RI^-/- mice develop glucose intolerance and IR after 6mo HFD intervention. While mature-onset obesity is evident in LFD-IL-1RI^-/- mice, the additional metabolic insult of HFD was required to drive adipose inflammation and systemic IR. These findings indicate an important interaction between dietary fat and IL-1, relevant to optimal metabolic health.