We have demonstrated, using a combination of nuclear run-off and poly(A) site competition assays, that transcriptional termination occurs between the closely spaced human complement genes, C2 and Factor B, soon after the C2 poly(A) site. A comparison of the C2 termination signal with a functionally similar sequence downstream of the human alpha 2 globin gene reveals that both signals function in an orientation dependent manner, with subfragments of the whole signal displaying partial effects. In the case of the C2 termination sequence a protein binds within it, and is partially responsible for the termination effect. We further demonstrate that the same (or closely related) protein binds to the ME1a1 site in the murine c-myc promoter, which has been implicated in c-myc attenuation. We suggest that the termination/pause sequences positioned downstream of a gene's poly(A) site may constitute the general signals that elicit transcriptional termination in genes transcribed by RNA polymerase II.