Over the next two years, "Willis A. Lee" was twice deployed to the Mediterranean for operations with the 6th Fleet, separating those tours with local operations out of Newport and in the Caribbean and off the coast of Florida, primarily on ASW and air defense exercises. In the summer of 1959, she participated in Operation "Inland Sea" as flagship for Rear Admiral E. B. Taylor, Commander, Task Force 47, on a cruise on the Great Lakes. During that historic voyage, she transited the newly opened St. Lawrence Seaway and visited the ports of Chicago, Illinois; Milwaukee, Wisconsin; Detroit, Michigan; Erie, Pennsylvania; and Cleveland, Ohio. That autumn, "Willis A. Lee" returned to her schedule of maneuvers and exercises in the North Atlantic.