The ability of FK506 and cyclosporine to prolong mouse skin allograft survival when given alone and in combination was studied during primary and secondary responses. The drugs were efficient immunosuppressants of both types of anti-graft responses but--as reported earlier--much lower FK506 doses were required to produce those effects. Both agents synergized when administered together during primary responses but not secondary responses. This suggests that the combination treatment may be less successful in a presensitized host, a finding with potential clinical application.