Abstract: A mercaptoacetyl hydroxymethy-polyacrylamide (MAMPAM) flocculant with the ability to chelate heavy metal ions was prepared using polyacrylamide (PAM) and mercaptoacetyl acid (TGA) as main raw materials. The central composite design (CCD) of response surface methodology (RSM) was used to study the optimal flocculation conditions of Cu(Ⅱ) in water samples with MAMPAM. The results showed that: (1) The experimental values and response values were basically linear. The determination coefficient (R²) was 0.9154, and the residual error obeyed the normal distribution, indicating that the rationality and fitting of model were well. The F value and P value of the model were 12.75 and 0.0002 (<0.001), respectively, indicating that the model was highly significant. (2) The P values of the initial pH value (X₁), the initial Cu(Ⅱ) concentration (X₂) and the ratio of the dosage of MAMPAM to the initial Cu(Ⅱ) concentration (X₃) were 0.0034, 0.0732, and 0.0005, respectively, indicating that the X₁ and X₃ were significant influential factors, but the X₂ was not a significant factor. Through response surface analysis, the interactions of X₁X₃ and X₂X₃ were significant, but the interaction of X₁X₂ was not significant. (3) The optimal flocculation conditions were recommended by employing the software, and the conditions were as follows: the initial pH value of water sample was 5.8, the initial concentration of Cu(Ⅱ) was 65.6 mg/L, and the ratio of the MAMPAM dosage to the initial concentration of Cu(Ⅱ) was 3.7∶1. Under these flocculation conditions, the experimental value of the removal rate of Cu(Ⅱ) was 95.05%, and the predicted value of the removal rate of Cu(Ⅱ) was 98.52%. The relative deviation was −3.52%. The results show that RSM can be used to optimize the flocculation conditions of Cu(Ⅱ) treated with MAMPAM.