Limited epidemiologic evidence links cancer risk to dietary acid load and methionine intake. Acid stress and metabolic acidosis are closely related to cancer development. Methionine is the main acidogenic amino acid and exerts epigenetic influences. We recently reported preliminary results on dietary acid load, methionine intake, and breast cancer risk. Therefore, both variables deserve further epidemiologic analysis. We revisited a Uruguay-based case-control study (572 cases/2,294 matched controls); women were recruited from 4 central hospitals, and all were interviewed using a specific questionnaire. Food-derived nutrients were calculated from available databases. Dietary acid load was estimated based on a validated formula: the potential renal acid load (PRAL) score. OR was estimated by logistic regression, adjusting for potential confounders. We found significant, direct associations between the breast cancer risk and PRAL (OR = 3.33) and methionine intake (OR = 5.87). Trends were significant (P < 0.001).PRAL and methionine displayed higher ORs among subsets with a positive family history of cancer compared to a negative one:OR = 6.16 vs. 2.80 (PRAL); OR = 11.8 vs. 4.86 (methionine). Both estimates were higher in pre- than postmenopausal women: OR = 5.91 vs. 2.96 (PRAL); OR = 8.76 vs. 5.39 (methionine). In conclusion, an acidogenic dietary style may increase a breast cancer risk. Furthermore, our findings suggest that methionine intake, showing comparable or even higher ORs than the dietary acid load scores themselves, might influence the risk associated with acid-base imbalance, ultimately leading to cancer. Additional research on methionine-induced epigenetic influences is warranted.