Fatty acid taste (FAT) perception is involved in the regulation of dietary fat intake, where impaired FAT is associated with increased fatty food intake. There are a number of FAT receptors identified on human taste cells that are potentially responsible for FAT perception. Manipulating dietary fat intake, and in turn FAT perception, would elucidate which receptors are associated with long-term regulation of FAT perception. This study aimed to assess associations between diet-mediated changes to FAT receptors and FAT perception in humans. A co-twin randomized controlled trial was conducted, where each matching twin within a pair were randomly allocated to either an 8-week low-fat (LF; <20% energy fat) or high-fat (HF; >35% energy fat) diet. At baseline and week 8, fungiform papillae were biopsied in the fasted state and FAT receptor gene expressions (CD36, FFAR2, FFAR4, GPR84 and KNCA2) were measured using RT-PCR; and fatty acid taste threshold (FATT) was assessed using 3-alternate forced choice methodology. Linear mixed models were fitted, adjusting for correlation between co-twins. Intakes were compliant with the study design, with the LF and HF groups consuming 14.8% and 39.9% energy from fat, respectively. Expression of FFAR4 increased by 38% in the LF group (P=0.023; time-diet interaction P=0.063). Δ FFAR4 (Δ, week 8 – baseline) was associated with Δfat intake (g) (ˆβ=-159.4; P<0.001) and ΔFATT (ˆβ=-8.8; P=0.016). In summary, FFAR4 is involved in long-term diet-mediated changes to FAT perception. Manipulating dietary fat intake, and therefore FFAR4 expression, might aid in reducing taste-mediated passive overconsumption of fatty foods.