Background: Occult MI and met BC may be under-staged. Circulating cfDNA may be a dynamic, low-cost and minimally invasive biomarker. We evaluated correlations between total circulating cfDNA and presence of MIBC and met BC. We hypothesized that the relative abundance of circulating low molecular weight cfDNA would correlate with BC stage. Methods: Peripheral blood from pts with BC was collected in Streck BCT tubes and processed to obtain cf nucleic acid extracts. Total cfDNA quantity (ng/ml) was assessed by fluorimetry. cfDNA fragment size was measured by Bioanalyzer DNA analysis. Wilcoxon rank sum test and Fisher’s Exact test were used to compare cfDNA quantity and fragmentation pattern among pts with NMIBC, MIBC, met BC. Results: Blood was obtained from 58 pts with BC (20% women, 34% never smokers, median age 71 (29-89). There was no significant difference in cfDNA between MIBC and met BC, however, it was significantly lower in pts with NMIBC vs MIBC and met BC (table). The concentration of low molecular weight fragments (LMW-frags) (100 - 400) base pairs and the ratio of LMW-Frag to cfDNA were significantly different between pts with NMIBC and pts with MIBC or met BC (table). Using median values as the cutoff, there was a significantly higher proportion of pts with cfDNA > 7 ng/ml and LMW-frags > 1.6 ng/mL, in MIBC & met BC vs NMIBC (p < 0.001). The % of pts with LMW-frags to cfDNA > 30%, was significantly different among NMIBC, MIBC and met BC groups: 16%, 53%, 78%, respectively (p < 0.001). Conclusions: This exploratory study suggests that cfDNA levels may correlate with BC stage. Measuring the relative abundance of LMW-frags with the expected size of cf DNA can enhance the specificity of cfDNA analysis for distinction between MIBC and met BC. Further studies are needed to confirm findings and define the optimal cut-points for optimal BC staging.