Abstract Objective Large inter-individual variations exist in changes in inflammation and insulin resistance (IR) in response to hypocaloric-interventions in obese subjects that are not explained by weight-loss per se. We identified the number of serum apoB-lipoproteins (serum apoB) as the primary predictor of inflammatory markers in post-menopausal overweight/obese women. As apoB-lipoproteins are related to inflammation and inflammation promotes IR, we hypothesized that the reduction in inflammation and IR following hypocaloric-interventions is associated with the reduction in serum apoB. Methods/results After a 6-month hypocaloric-dietary-intervention in 56 overweight/obese post-menopausal women, there was a significant reduction in weight, total, subcutaneous abdominal and visceral abdominal fat mass, apoB, Lp(a), hsCRP, orosomucoid, haptoglobin and IR (increased M clamp) and an increase in LDL-C/apoB ratio. In regression analysis, % change in apoB was the primary predictor of % changes in hsCRP ( R 2 = 0.22), orosomucoid ( R 2 = 0.35), haptoglobin ( R 2 = 0.43) and M clamp ( R 2 = 0.17). When the study population was split around baseline median apoB (0.97 g/L), women who were above median apoB ( N = 27) had significant reduction in apoB (−17%), hsCRP (−24%), orosomucoid (−8%), haptoglobin (−18%) and IR ( M clamp +14%). On the other hand, women below median apoB ( N = 29) had no significant changes in these parameters despite equivalent reduction in weight and fat depots in the two groups. Conclusion Reduction in apoB associated strongly and independently with the reduction in inflammatory markers and IR following a hypocaloric-diet in overweight/obese women. We hypothesize that the elevated apoB phenotype may be key therapeutic target to reduce obesity-associated inflammation and IR maximally by hypocaloric-dietary-interventions.