Background: Altered fat distribution and chronic inflammation are found in both persons living with HIV (PLWH) and persons with diabetes mellitus type 2 (DM2) and are known risk factors for cardiovascular diseases (CVD). We aimed to investigate if a synergistic effect of HIV infection and DM2 was found on fat distribution and inflammation. Methods: A cross-sectional study was performed including PLWH with HIV RNA < 200 copies/mL (18 with DM2 (HIV + DM2+), 18 without DM2 (HIV + DM2-)) and controls (19 with DM2 (controls with DM2) and 25 without DM2 (healthy controls). We measured fat distribution using dual-energy X-ray absorptiometry scan. Plasma concentrations of adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF- α) and soluble CD14 (sCD14) was measured using snap-frozen plasma. Results: HIV + DM2+ and HIV + DM2- had comparable trunk/limb fat ratio. In contrast, HIV + DM2+ had a higher trunk/ limb fat ratio than controls with DM2 and healthy controls (p = 0.013 and p < 0.001, respectively). However, HIV + DM2+ and controls with DM2 had comparable amount of trunk fat mass (kg) (p = 0.254). A lower concentration of plasma adiponectin and higher concentration of IL-6 was found in HIV + DM2+ than in HIV + DM2-(p = 0.037 and p = 0.039) and in healthy controls (p = 0.001 and p = 0.012). In contrast, plasma adiponectin and IL-6 concentrations were comparable in HIV + DM2+ and controls with DM2 (p = 0.345 and p = 0.825). Concentration of sCD14 was comparable in HIV + DM2+ and HIV + DM2–(p = 0.850), but elevated in HIV + DM2+ compared to controls with DM2 (p < 0.001) and healthy controls (p = 0.007). No statistical interactions were found between HIV infection and DM2 for any of the depending variables. Conclusion: A synergistic effect of HIV and DM2 was not found for any of the outcomes. However, HIV + DM2+ had features related to both HIV infection and DM2 with a high trunk/limb ratio, high trunk fat mass, low concentration of plasma adiponectin and elevated concentrations of IL-6 and sCD14. This could contribute to elevated risk of CVD.