Borrelia burgdorferi-infected ticks were fed on either OspC-immunized mice or normal, nonimmunized mice. After 72 h, the ticks were detached, followed by dissection and subsequent culturing in Barbour-Stoenner-Kelley II medium of the salivary glands from each tick to determine the presence of borreliae. Forty percent (10 of 25) of salivary glands from ticks that had fed on nonimmunized mice were culture positive, while only 7.4% (2 of 27) of salivary glands from ticks that had fed on OspC-immunized mice were culture positive, thus indicating a much reduced borrelial migration from the midgut when the bloodmeal contained anti-OspC antibodies. Fluorescent antibody staining of the corresponding midguts from ticks that had fed on the OspC-immunized mice showed that borreliae were present but did not produce OspC. In contrast, borreliae in midguts from ticks that had fed on normal mice demonstrated substantial ospC expression. This study provides evidence that, during tick feeding on an OspC-immunized host, transmission of borreliae from the tick is prevented; it also suggests that OspC functions in a tick-to-host transmission mechanism.