Soil erosion had decreased the land productivity by declining soil depth, removing nutrient element, consequently altering soil physico-chemical properties and biological status, which retarded plant colonization and growth in karst rocky desertification regions. Being rich in organic matter and other nutrients element, municipal sewage sludge (SS) was widely used as an amendment to improve soil fertility. An experiment was conducted to investigate the effect of SS application on the soil quality in a typical karst desertification area, Xingren County of Guizhou Province, Southwest. China. In this study, 20 similar to 75% dosage of SS were added to soil. The soil organic matter (SOM), total and available nutrients, microbial biomass carbon and nitrogen ((MBC and MBN), and the soil enzymatic activities were examined. SOM, total and available nitrogen (N) and phosphorus (P), microbial biomass, activities of dehydrogenase, catalase, cellulose, ivertase, urease and alkaline phosphatase significantly increased with SS addition. The content of organic matter and other nutrients increased with the SS addition rate increasing. However, MBC, MBN and the activities of cellulase, ivertase and urease showed a decrease trend while the SS application rate was above 35%. Therefore, the higher contents of organic matter, N and P could not indicate the higher soil quality. The results convincingly demonstrated that the lower rate of SS application (20 similar to 35%) would take advantage of favorable effects on the soil fertility in karst desertification regions.