Both End in Speculation begins with two discoveries: a murdered woman found on the Arch of Constantine and the revelation of a John Keats' poem written at the end of his life in Rome, Italy. Disclosure of the invaluable poem causes events leading to murders with bodies deposited at historical sites in Rome.

The Vena Goodwin mystery is also an exploration of Keats' concept of "negative capability," in which intuition and uncertainty are prized over absoluteness. The speculation refers to light and darkness in the plot, bringing in the European refugee crisis, the Keats' poem, and why we seek out uncertainties, including mystery.
Familiar characters from book one in the series are the protagonist Vena Goodwin and her Italian lover Elio Canestrini.