: Flotation performance in plants can significantly be affected by seasonal variations in different parts of the world. This is generally attributed to the changes in water temperature and pulp temperature in flotation plants, type and concentration of dissolved ions in process water. Extreme temperature conditions may be the major factor affecting flotation performance and mask the influence of water chemistry. Therefore, the interactive effects of the temperature and water chemistry should be taken into consideration, particularly for mine sites experiencing extreme temperature conditions. In this paper, effects of temperature, sulphate (SO42-), thiosulphate (S2O32-) and calcium (Ca2+) ions on the flotation performance of a Cu-Pb-Zn complex sulfide ore were investigated using a statistical experimental design and modelling approach. Batch scale kinetic flotation tests were conducted using the sequential flotation flowsheet of a bulk Cu-Pb flotation stage followed by a zinc rougher flotation stage. The results of the zinc flotation section were used for the statistical evaluation since the zinc concentrate was the product with an economic value for the mine. The results were evaluated using ANOVA analysis and regression analysis to determine the significant parameters and derive individual regression models for each flotation response with Design Expert software version 6.0.8. Individual regression models were developed using the significant main effects and their interactions for each flotation response. Then, the models were used to determine the concentration of the dissolved ions and pulp temperature required to achieve the maximum zinc recovery, maximum zinc grade or the optimum zinc grade and recovery. The details of statistical experimental design, discussions on the effects of the experimental factors and their interactions on the flotation performance and development of regression models are discussed in this paper.