Simple Summary: No clinical studies have investigated the effect of radioiodine (131I)-targeted therapy on the potential markers of ongoing inflammation in patients with DTC associated with T2DM and obesity. To our knowledge, this is the first study to report the relationship between prescribed 131I activity, blood radioactivity, BMI, and neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios measured three days after 131I intake in DTC with/without T2DM patients. The strong correlation measured between blood radioactivity and high BMI, without a correlation between blood radioactivity and the 131I dose, proves a possible connection between 131I uptake in the bloodstream and chronic inflammation, the so-called "perfect storm", specific to T2DM. Considering the immune response to 131I therapy, the two groups of patients can be seen as a synchronous portrait of two sides: in patients without T2DM, if 131I therapy has immunosuppressive effects, in the chronic inflammation context of T2DM, 131I therapy amplifies immune metabolism. No clinical studies have investigated the effect of radioiodine (131I)-targeted therapy on the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as inflammatory response markers in patients with differentiated thyroid cancer (DTC) associated with type 2 diabetes mellitus (T2DM) and obesity. This study aimed to assess the relationship between blood radioactivity, body mass index (BMI), and peripheral blood cells three days after 131I intake in 56 female patients without T2DM (DTC/−T2DM) vs. 24 female patients with T2DM (DTC/+T2DM). Blood radioactivity, measured three days after 131I intake, was significantly lower in the DTC/+T2DM than in the DTC/−T2DM patients (0.7 mCi vs. 1.5 mCi, p < 0.001). The relationship between blood radioactivity and BMI (r = 0.83, p < 0.001), blood radioactivity and NLR (r = 0.53, p = 0.008), and BMI and NLR (r = 0.58, p = 0.003) indicates a possible connection between the bloodstream 131I uptake and T2DM-specific chronic inflammation. In patients without T2DM, 131I therapy has immunosuppressive effects, leading to increased NLR (19.6%, p = 0.009) and PLR (39.1%, p = 0.002). On the contrary, in the chronic inflammation context of T2DM, 131I therapy amplifies immune metabolism, leading to a drop in NLR (10%, p = 0.032) and PLR (13.4%, p = 0.021). Our results show that, in DTC/+T2DM, the bidirectional crosstalk between neutrophils and obesity may limit 131I uptake in the bloodstream. Considering the immune response to 131I therapy, the two groups of patients can be seen as a synchronous portrait of two sides. The explanation could lie in the different radiosensitivity of T and B lymphocytes, with T lymphocytes being predominant in patients with DTC/−T2DM and, most likely, B lymphocytes being predominant in T2DM. [ABSTRACT FROM AUTHOR]