© 2016 The Obesity Society Objective: Diet-induced obesity has been shown to alter immune function in mice, but distinguishing the effects of obesity from changes in diet composition is complicated. It was hypothesized that immunological differences would exist between diet-induced obese (DIO) and obese-resistant (OB-Res) mice fed the same high-fat diet (HFD). Methods: BALB/c mice were fed either standard chow or HFD to generate lean or DIO and OB-Res mice, respectively. Resulting mice were analyzed for serum immunologic and metabolic profiles and cellular immune parameters. Results: BALB/c mice on HFD were categorized as DIO or OB-Res, based on body weight versus lean controls. DIO mice were physiologically distinct from OB-Res mice, whose serum insulin, leptin, gastric inhibitory polypeptide, and eotaxin concentrations remained similar to lean controls. DIO mice had increased macrophage+ crown-like structures in white adipose tissue, although macrophage percentages were unchanged from OB-Res and lean mice. DIO mice also had decreased splenic CD4+ T cells, elevated serum GM-CSF, and increased splenic CD11c+ dendritic cells, but impaired dendritic cell stimulatory capacity (P < 0.05 vs. lean controls). These parameters were unaltered in OB-Res mice versus lean controls. Conclusions: Diet-induced obesity results in alterations in immune and metabolic profiles that are distinct from effects caused by HFD alone.