A Case of Conscience is a science fiction novel by James Blish, first published in 1958. It is the story of a Jesuit who investigates an alien race that has no religion; they are completely without any concept of God, an afterlife, or the idea of sin; and the species evolves through several forms through the course of its life cycle. The story was originally published as a novella in 1953, and later extended to novel-length, of which the first part is the original novella. The novel is the first part of Blish's thematic "After Such Knowledge" trilogy, followed by Black Easter/The Day After Judgment and Dr Mirabilis.

The story is unusual in several respects. Few science fiction stories of the time attempted religious themes, and still fewer did this with Catholicism. Some of the first part is taken up with the Jesuit's attempt to solve a puzzle, a long description of scandalous intrigue between various pseudonymous characters. As he is about to leave for Earth, he realizes the puzzle is soluble. The puzzle is contained within the pages of Finnegans Wake, by James Joyce.

Many reacted negatively to the story, but surprisingly few educated Catholics were among them. One even sent James Blish a copy of the actual Church guidelines for dealing with extraterrestrials. These are not detailed, but merely suggest overall strategy based on whether the beings have souls or not, and if they have them, whether they are fallen like humans, or exist in a state of grace.

Won Hugo Award for Best Novel in 1959.