We have assembled and assessed the statistical procedure which is capable to objectively explore influence of the Danube's major tributaries (the Rivers Tisa, Sava, and Velika Morava) to its eco-chemical status. Procedure contains several tests for measurement of central tendencies: one-way analysis of variance (ANOVA), repeated measures ANOVA, and nonparametric Kruskal-Wallis and Mann-Whitney tests. Various nuisance factors, (outliers, departures from normality, seasonality, and heteroscedasticity) which are present in large data bases, affect the objectivity of central tendency tests; therefore, it was important not only to estimate their robustness, but also to apply proper procedures for detection of the nuisance factors (Grubbs', generalized ESD-extreme Studentized deviate, Kolmogorov-Smirnov, Shapiro-Wilk, turning point, Wald-Wolfowitz runs, Kendall rank, and Levene's tests) and to mitigate their influence (outlier exclusion, Box-Cox, and logarithmic transformations). The analysis of selected eco-chemical parameters: biological oxygen demand-5, chemical oxygen demand, UV extinction at 254 nm, dissolved oxygen, oxygen saturation, total dissolved solids, electrical conductivity, suspended matter, total phosphorus, phosphates, nitrates, ammonia, pH, total alkalinity, m-2p alkalinity, CO2, and temperature, was performed for 15 years period. The Tisa was the most polluted tributary, but its pollution load was not substantial enough to exceed the Danube self-purification potential. The City of Belgrade was also identified as serious pollution source. Assessment of assembled statistical procedure, which was based on the real environmental data, indicates that proposed tests are sufficiently robust to the observed level of nuisance factors with the exception of pronounced seasonality.