The Commentary in eighteen books, each with its Preface. It was written in the years 404-410, and addressed to Eustochium alone, her mother Paula having died in 404.

The Preface to Book i. touches generally upon the character and contents of Isaiah, asserting that many of the prophecies are directly applicable to Christ, and that the nations who are dealt with have a spiritual meaning. Those to the following books mostly give a short statement of the contents of the chapters commented on, and entreat the prayers of Eustochium for the work. The Fifth Book (or chapters xiii. to xxiii.) had been published before by itself, at the instance of a bishop named Amabilis, but he says he must add the metaphorical and spiritual meaning of the Visions of the various nations, which is done in Books vi. and vii. The Preface to Book x. contains a bitter allusion to Rufinus, "the Scorpion, a dumb and poisonous brute, still grumbling over my former reply," and speaks of Pammachius as joining in the request for the continuation of the Commentaries.

The Preface to Book xi. intimates that his commentary upon Daniel, which expounded the statue with feet of iron and clay as the Roman Empire, and announced its fall, had been known at the court and resented by Stilicho, but that all danger from that source had been removed by the judgment of God, that is, through the death of Stilicho by the command of his son in-law Honorius. The Preface to Book xiii. records a severe illness which had stopped his work, though he was restored to health suddenly; and that to Book xiv. thanks Eustochium for her kind offices during this illness. The remaining Prefaces, though they have occasionally some interest in the history of the interpretation of Scripture, need not delay us.