OBJECTIVE Trimethylamine N-oxide (TMAO) is suggested as an independent gut microbiota–derived risk factor for cardiovascular and renal disease. We investigated associations between plasma TMAO concentrations and cardio-renal outcomes in a prospective study of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS Plasma TMAO was measured at baseline in 1,159 individuals with type 1 diabetes (58% male, mean ± SD age 46 ± 13 years). End points were all-cause and cardiovascular mortality, cardiovascular disease (CVD), and renal events tracked from national registries. Associations between TMAO and end points were tested using Cox regression models. RESULTS After 15.0 (6.7–19.3) (median [interquartile range]) years of follow-up, we recorded all-cause and cardiovascular mortality (n = 363 and 120, respectively), combined CVD (n = 406), coronary outcome (myocardial infarction and coronary intervention) (n = 163), stroke (n = 115), hospitalization for heart failure (n = 81), and end-stage renal disease (n = 144). In univariate analyses, higher TMAO concentrations were associated with all end points (P ≤ 0.005). Except for stroke and heart failure, all end points remained significantly associated with higher TMAO concentrations after adjustment for conventional cardiovascular risk factors (P ≤ 0.003). After further adjustment for baseline estimated glomerular filtration rate (eGFR), results became insignificant for all end points. TMAO was inversely associated with baseline eGFR (R2 = 0.29; P < 0.001). CONCLUSIONS In individuals with type 1 diabetes, higher concentrations of plasma TMAO were associated with mortality, CVD events, and poor renal outcome, independent of conventional risk factors. However, the association became insignificant after further adjustment for baseline eGFR. This could reflect TMAO as a renal function marker or a risk factor for micro- and macrovascular complications mediated through impaired renal function.