<i>Background:</i> Long-term maintenance of a dietary-induced weight loss continues to be a major health problem and warrants research on innovative approaches to understand weight stability. We investigated the role of the proinflammatory status on weight changes in obese subjects receiving a low-calorie diet (LCD) and during the subsequent 6-month weight maintenance period. <i>Methods:</i> Eighty-four subjects (age: 34.2 ± 0.53 years; body mass index, BMI: 30.4 ± 1.8 kg/m²) followed an 8-week LCD intervention and were contacted again 6 months later. Body composition, circulating proinflammatory markers [tumor necrosis factor (TNF)α, interleukin-6, C-reactive protein and leptin] and mRNA levels of inflammation-related genes [TNFα and nuclear factor (NF) κBtranscription subunits] in peripheral blood mononuclear cells (PBMC) were evaluated. <i>Results:</i> The 6-month weight regain was predicted by high concentrations of TNFα at LCD completion (OR = 4.21, p = 0.036) along with the baseline amount of fat mass (OR = 7.23, p = 0.029). In addition, baseline leptin concentrations (p = 0.028) as well as mRNA levels of TNFα and NFκB subunits were higher at the end of the dietary intervention (p < 0.05) in PBMC of subjects who regained ≥10% of the dietary-induced weight loss. <i>Conclusions:</i> These findings demonstrate a role for the proinflammatory state and body adiposity in the prediction of weight-loss regain. This relationship could contribute to the design of more personalized nutritional treatments in obese patients and favor the weight maintenance process.