The potential offered by the intra-body communication (IBC) over the past few years has resulted in a spike of interest for the topic, specifically for medical applications. Fat-IBC is subsequently a novel alternative technique that utilizes fat tissue as a communication channel. This work aimed to identify such transmission medium and its performance in varying blood-vessel systems at 2.45 GHz, particularly in the context of the IBC and medical applications. It incorporated three-dimensional (3D) electromagnetic simulations and laboratory investigations that implemented models of blood vessels of varying orientations, sizes, and positions. Such investigations were undertaken by using ex-vivo porcine tissues and three blood-vessel system configurations. These configurations represent extreme cases of real-life scenarios that sufficiently elucidated their principal influence on the transmission. The blood-vessel models consisted of ex-vivo muscle tissues and copper rods. The results showed that the blood vessels crossing the channel vertically contributed to 5.1 dB and 17.1 dB signal losses for muscle and copper rods, respectively, which is the worst-case scenario in the context of fat-channel with perturbance. In contrast, blood vessels aligned-longitudinally in the channel have less effect and yielded 4.5 dB and 4.2 dB signal losses for muscle and copper rods, respectively. Meanwhile, the blood vessels crossing the channel horizontally displayed 3.4 dB and 1.9 dB signal losses for muscle and copper rods, respectively, which were the smallest losses among the configurations. The laboratory investigations were in agreement with the simulations. Thus, this work substantiated the fat-IBC signal transmission variability in the context of varying blood vessel configurations.