Purpose: To investigate the role of in vivo confocal microscopy (IVCM) in the detection of inflammatory activity and follow-up of herpetic stromal keratitis (HSK). Design: Prospective observational cohort study. Participants: Thirty-eight patients with active HSK. Methods: Within 7 days after diagnosis of active HSK, both eyes of each patient were examined by slit-lamp biomicroscopy and white-light IVCM (Confoscan 4; Nidek Technologies, Padova, Italy). The HSK-affected eyes were followed up at 1, 3, 6, and 12 months, whereas the unaffected fellow eyes were reexamined after 12 months. Three patients did not complete follow-up and were excluded for data analyses. All IVCM examinations were assessed for morphologic alterations characteristic of inflammatory Main Outcome Measures: Presence of dendriform cells, pseudoguttae, and keratic precipitates, and follow-up of mean corneal backscatter. Results: An increase of dendriform cells and pseudoguttae often accompanied stromal infiltration. Because these IVCM parameters were indiscernible or overlooked at slit-lamp examination, they proved to be excellent indicators of inflammatory activity. At 12 months' follow-up, mean corneal backscatter had decreased significantly by 36%, but still fell outside the normal range in 24 (69%) of the HSK-affected eyes. By using slit-lamp in conjunction with IVCM, we detected 17 recurrences in 14 of 35 Conclusions: The data presented demonstrate that IVCM is complementary to slit-lamp examination in the follow-up of HSK, particularly because of its power to detect early signs of intracorneal inflammatory activity. Therapy guidance based on morphologic assessment and corneal backscatter measurement by combined IVCM and slit-lamp examination may improve the outcome of HSK. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:1102-1110 (C) 2012 by the American Academy of Ophthalmology.