To reduce severe fluoropyrimidine-related toxicity, pharmacogenetic guidelines recommend a dose reduction for carriers of four high-risk variants in the gene (*2A, *13, c.2846A>T, HapB3). The polymorphism in the gene has been shown to enhance the predictive value of these variants. Our study aimed to explore whether rs895819 in the gene modifies the effect of five common variants: c.1129-5923C>G (rs75017182, HapB3), c.2194G>A (rs1801160, *6), c.1601G>A (rs1801158, *4), c.496A>G (rs2297595), and c.85T>C (rs1801265, *9A). The study included 370 Caucasian patients with gastrointestinal tumors who received fluoropyrimidine-containing chemotherapy. Genotyping was performed using high-resolution melting analysis. The *6 allele was associated with overall severe toxicity and neutropenia with an increased risk particularly pronounced in patients carrying the variant. All carriers of *6 exhibited an association with asthenia regardless of their status. The increased risk of neutropenia in patients with c.496G was only evident in those co-carrying the variant. *4 was also significantly linked to neutropenia risk in co-carriers of the variant. Thus, we have demonstrated the predictive value of the *6, *4, and c.496G alleles of the gene, considering the modifying effect of the polymorphism.