Response to antidepressant treatment is highly variable with some patients responding within a few weeks, whereas others have to wait for months until the onset of clinical effects. Gene expression profiling may be a tool to identify markers of antidepressant treatment response and new potential drug targets. In a first step, we selected 12 male, age- and severity-matched pairs of remitters and nonresponders, and analyzed expression profiles in peripheral blood at admission and after 2 and 5 weeks of treatment using Illumina expression arrays. We identified 127 transcripts significantly associated with treatment response with a minimal P-value of 9.41 × 10(-)(4) (false discovery rate-corrected). Analysis of selected transcripts in an independent replication sample of 142 depressed inpatients confirmed that lower expression of retinoid-related orphan receptor alpha (RORa, P=6.23 × 10(-4)), germinal center expressed transcript 2 (GCET2, P=2.08 × 10(-2)) and chitinase 3-like protein 2 (CHI3L2, P=4.45 × 10(-2)) on admission were associated with beneficial treatment response. In addition, leukocyte-specific protein 1 (LSP1) significantly decreased after 5 weeks of treatment in responders (P=2.91 × 10(-2)). Additional genetic, in vivo stress responsitivity data and murine gene expression findings corroborate our finding of RORa as a transcriptional marker of antidepressant response. In summary, using a genome-wide transcriptomics approach and subsequent validation studies, we identified several transcripts including the circadian gene transcript RORa that may serve as biomarkers indicating antidepressant treatment response.