Understanding the toxicity of silica nanoparticles (SiO(2)) on the cellular level is crucial for rational design of these nanomaterials for biomedical applications. Herein, we explore the impacts of geometry, porosity, and surface charge of SiO(2) on cellular toxicity and hemolytic activity. Nonporous Stöber silica nanospheres (115 nm diameter), mesoporous silica nanospheres (120 nm diameter, aspect ratio 1), mesoporous silica nanorods with aspect ratio of 2, 4, and 8 (width by length 80 × 200 nm, 150 × 600 nm, 130 × 1000 nm), and their cationic counterparts were evaluated on macrophages, lung carcinoma cells, and human erythrocytes. It was shown that the toxicity of SiO(2) is cell-type dependent and that surface charge and pore size govern cellular toxicity. Using inductively coupled plasma mass spectrometry, the cellular association of SiO(2) was quantitated with the association amount increasing in the following order: mesoporous SiO(2) (aspect ratio 1, 2, 4, 8) < amine-modified mesoporous SiO(2) (aspect ratio 1, 2, 4, 8) < amine-modified nonporous Stöber SiO(2) < nonporous Stöber SiO(2). Geometry did not seem to influence the extent of SiO(2) association at early or extended time points. The level of cellular association of the nanoparticles was directly linked to the extent of plasma membrane damage, suggesting a biological cause-and-effect relationship. Hemolysis assay showed that the hemolytic activity was porosity- and geometry-dependent for bare SiO(2) and surface-charge-dependent for amine-modified SiO(2). A good correlation between hemolytic activity and cellular association was found on a similar dosage basis. These results can provide useful guidelines for the rational design of SiO(2) in nanomedicine.