In this study, we evaluated the estimation of three important parameters for data collected in a multisite cluster-randomized trial (MS-CRT): the treatment effect, and the treatment by covariate interactions at Levels 1 and 2. The Level 1 and Level 2 interaction parameters are the coefficients for the products of the treatment indicator, with the covariate centered on its Level 2 expected value and with the Level 2 expected value centered on its Level 3 expected value, respectively. A comparison of a model-based approach to design-based approaches was performed using simulation studies. The results showed that both approaches produced similar treatment effect estimates and interaction estimates at Level 1, as well as similar Type I error rates and statistical power. However, the estimate of the Level 2 interaction coefficient for the product of the treatment indicator and an arithmetic mean of the Level 1 covariate was severely biased in most conditions. Therefore, applied researchers should be cautious when using arithmetic means to form a treatment by covariate interaction at Level 2 in MS-CRT data.