Inhalation of quartz particles is associated with a variety of adverse lung effects. Since particle surface is considered to be crucial for particle pathogenicity, we investigated the influence of quartz surface properties on lung burden, inflammation (bronchoalveolar lavage cells), and cytotoxicity (protein, lactate dehydrogenase, beta-glucuronidase) 90 days after a single intratracheal instillation of 2 mg DQ12 into rats. The role of particle surface characteristics was investigated by comparative investigation of native versus surface-modified quartz, using polyvinylpyridine N-oxide (PVNO) or aluminum lactate (AL) coating. Uptake and subcellular localization of quartz samples as well as tumor necrosis factor (TNF)-alpha release were determined using NR8383 rat alveolar macrophages. Surface modification of quartz particles resulted in marked in vivo and in vitro changes. Compared to native quartz, modified quartz samples showed lower lung burden at 90 days, as well as decreased inflammatory and cytotoxic responses. Coating with polyvinylpyridine N-oxide (PVNO) appeared to be more effective than aluminium lactate (AL). PVNO-coating of quartz also resulted in an enhanced particle uptake by macrophages up to 24 h, whereas AL coating caused a transient reduction of quartz uptake at 2 h. At 24 h differences with the native quartz were absent. Subcellular localization of quartz particles was not affected by surface modifications. However, surface modification resulted in a reduced release of TNF-alpha. In conclusion, surface properties of quartz particles appear to be crucial for rate and extent of in vitro particle uptake in macrophages. Our in vivo findings also indicate that quartz surface properties may affect clearance kinetics. Particle surface-specific interactions between quartz and macrophages may therefore play a major role in the pulmonary pathogenicity of quartz.