The clinical success of calcium phosphate bone grafts (CPs) largely depends on the body’s immune response. However, traditional biocompatibility tests use healthy organisms and cannot predict effectiveness in patients with common chronic inflammatory diseases. This study examines how inflammation modulates the immune response, in vitro and in vivo, to low-temperature biomimetic CPs: dicalcium phosphate dihydrate (DCPD), octacalcium phosphate (OCP), and hydroxyapatite (HAp). In vitro studies involved human monocytes, macrophages, lymphocytes, and mesenchymal stromal cells (MSCs), with or without pro-inflammatory activation. In vivo biocompatibility was assessed via subcutaneous implantation in rats, with or without Complete Freund’s Adjuvant (CFA)-induced inflammation. Under normal conditions, all CP caused minimal immune reactivity. Inflammation-activated macrophages, however, triggered an acute reaction with significantly increased TNF-α and IL-1β secretion. Healthy and inflamed animals showed sharp contrasts. Although all materials exhibited thickened fibrous capsules during inflammation, biocompatibility varied markedly: DCPD performed best by promoting angiogenesis with minimal inflammation; HAp provoked the most severes response, including tissue necrosis and signs of rejection; OCP showed intermediate effects, with angiogenesis but notable fibrosis. Inflammatory processes critically influence CP biocompatibility; materials biocompatible in healthy organisms can induce fibrosis or rejection under inflammation. Disease-relevant, immune-challenged models are essential to predict clinical efficacy and safety.