Recent experimental studies have suggested that galectin-3 has an interaction with aldosterone, and modifies its adverse effects. We therefore aimed to elucidate whether the relationship between plasma aldosterone concentrations (PACs) and long-term fatal cardiovascular (CV) events would depend on plasma galectin-3 levels. A total of 2,457 patients (median age: 63.5 [interquartile range (IQR) = 56.3 to 70.6] years, 30.1% women) from the LUdwigshafen RIsk and Cardiovascular Health study, with a median follow-up of 9.9 (IQR = 8.5 to 10.7) years, were included. We tested the interaction between aldosterone and galectin-3 for CV-mortality using a multivariate Cox proportional hazard model, reporting hazard ratios (HRs) with 95% confidence intervals (95%CIs). Adjustments for multiple CV risk factors as well as medication use were included. Mean PAC was 79.0 (IQR = 48.0 to 124.0) pg/ml and there were 558 (16.8%) CV deaths. There was a significant interaction between PAC and galectin-3 (p = 0.021). When stratifying patients by the median galectin-3, there was a significant association between aldosterone and CV-mortality for those above (HR per 1 standard deviation = 1.14; 95%CI [1.01 to 1.30], p = 0.023), but not below the cut-off value (HR per 1 standard deviation = 1.00; 95%CI [0.87 to 1.15], p = 0.185). In conclusion, the current study demonstrates for the first time a modifying effect of galectin-3 on the association between aldosterone and CV-mortality risk in humans. These findings indicate that galectin-3 is an intermediate between aldosterone and adverse outcomes.