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Background: Non-nutritive sweeteners (NNS) are chemical substances developed by the food industry to reduce sugar and calories while preserving sweetness. Epidemiological studies have indicated a potential increased risk of certain cancers, including breast cancer (BC), associated with NNS consumption. However, the evidence has exclusively relied on self-reported dietary information rather than objective measurements of NNSs. We examined the association of urinary concentrations of NNS with BC risk in women from the large Moli-sani Study. Methods: Using a case-cohort design, a sample of 988 middle-aged women (mean age 55 ± 12 y) was randomly selected as a sub-cohort and compared to 272 women with incident BC (38 premenopausal and 234 postmenopausal). A total of 6 commonly used NNSs (i.e., aspartame, acesulfame, saccharin, sucralose, cyclamate, and steviol glycosides) were measured through liquid chromatography-mass spectrometry in spot urine samples (creatinine-adjusted concentrations; µg/mg) collected at baseline (2005-2010). The multivariable hazard ratios (HRs) were estimated using weighted Cox regression models for the case-cohort design, with each NNS modelled as a binary variable (i.e., presence vs. absence). The sum of these values produced a total urinary NNS score, which could range from 0 to 6, and was further categorised as low (0-1) or high (2-5). Results: The predominant NNS detected in urine was saccharin (E954), contributing to 77% of total NNSs, followed by steviol glycosides (E960;11%). In multivariable-adjusted Cox analyses, neither individual NNSs nor total NNS urinary concentrations were associated with overall BC risk (HR = 1.09; 95% CI 0.80-1.48 for high vs. low). However, the presence of sucralose (E955) was directly linked to premenopausal BC (HR = 5.90; 95% CI 1.44-24.20; p = 0.014), although this estimate was based on only 38 cases and was imprecise. Conclusions: Urinary NNS concentrations were not associated with overall BC risk. The observed association between urinary sucralose and premenopausal BC should be considered exploratory and hypothesis-generating and requires independent replication.