In this study, the Response surface methodology (RSM) was used to describe the individual and interactive effects of two variables – initial Cd 2+ concentration and initial Ni 2+ concentration – at five levels. They were combined, under controlled conditions, according to a Central Composite Design (CCD) of the duckweed L. gibba. Parallelly, the assessment regarding the removal of the aforementioned compounds took place. The effects of initial Cd 2+ and initial Ni 2+ concentrations on the growth parameters, the photosynthetic pigment and the removal of heavy metals were part of the study. The results were statistically analyzed using JMP 9.0.2 (SAS Institute) software. A second-order quadratic model could approximate the mathematical relationship between responses and two significant independent variables which showed the influence of each variable and their interactions. The analysis of variance (Anova) revealed the relative significance of the process parameters in responses. Moreover, a high correlation was found between the experimental and the predicted results, reflected by R 2 (coefficient of determination). This study has demonstrated that RSM can be applied to predict the physiological responses of L. gibba and the heavy metal removal. The method applied for this research allowed obtaining the maximum of the information counting with a limited set of laboratory experiments.