There are several reports studying cell behavior on surfaces in 2D or in hydrogels in 3D. However, cell behavior in 3D microporous scaffolds has not been investigated extensively. In this study, poly(L-lactic acid)/poly(lactic acid-co-glycolic acid) (PLLA/PLGA)-based microporous scaffolds were used to study the effects of scaffold microarchitecture and mechanical properties on the behavior of two different cell types, human meniscal fibrochondrocytes and L929 mouse fibroblasts. In general, cell attachment, spreading and proliferation rate were mainly regulated by the strut (pore wall) stiffness. Increasing strut stiffness resulted in an increase in L929 fibroblast attachment and a decrease in fibrochondrocyte attachment. L929 fibroblasts tended to get more round as the strut stiffness increased, while fibrochondrocytes tended to get more elongated. Cell migration increased for both cell types with the increasing pore size. Migrating L929 fibroblasts tended to get more round on the stiff scaffolds, while fibrochondrocytes tended to get more round on the soft scaffolds. This study shows that the behavior of cells on 3D microporous scaffolds is mainly regulated by pore size and strut stiffness, and the response of a cell depends on the stiffness of both cells and materials. This study could be useful in designing better scaffolds for tissue engineering applications.