Aims CYP2D6 is a key enzyme for metabolizing tamoxifen into active metabolites, but polymorphisms in this enzyme lead to varying metabolic capacities. Increasing the tamoxifen dose in patients with deficient CYP2D6 metabolism can elevate endoxifen levels to those of patients with normal phenotypes. This study examines the impact of increasing the dose of tamoxifen on toxicity in poor metabolizers of the CYP2D6 enzyme. Methods Eighty-six breast cancer patients treated with tamoxifen were classified by CYP2D6 metabolizer phenotype according to Clinical Pharmacogenetics Implementation Consortium guidelines. All patients started with a 20 mg/day dose of tamoxifen, with poor metabolizers having their doses increased to 60 mg/day. Side effects, including osteoarticular pain, hot flashes, asthenia, and uterine changes, were analyzed using Kaplan-Meier analysis and the Cox proportional hazards regression model to assess the relationship between CYP2D6 metabolizer type and these side effects. Results Significant differences were found only in uterine changes among CYP2D6 metabolizer types in both the overall cohort and a subgroup selected via Propensity Score Matching (PSM). Rapid metabolizers exhibited a lower incidence of uterine changes (p < 0.001 in Kaplan-Meier analysis; HR 0.195, 95% CI: 0.07 - 0.52, p = 0.001) in the complete cohort. In the PSM cohort, Kaplan-Meier analysis showed a p-value of 0.001 with an HR of 0.07 (95% CI: 0.01 - 0.54, p = 0.011). Conclusion Tamoxifen dose scalation in patients with poor CYP2D6 metabolism may increase the occurrence of uterine changes but does not significantly affect the incidence of osteoarticular pain, hot flashes, or asthenia.