Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase (mHMG‐CoAS) is a key enzyme in ketogenesis, catalyzing the condensation of acetyl‐CoA and acetoacetyl‐CoA to generate HMG‐CoA, which is eventually converted to ketone bodies. Transcription of the nuclear‐encoded gene for mHMG‐CoAS is stimulated by peroxisome proliferator‐activated receptor (PPAR) α, a fatty acid‐activated nuclear hormone receptor. Here we show that the mHMG‐CoAS protein physically interacts with PPARα in vitro, and potentiates PPARα‐dependent transcriptional activation via the cognate PPAR response element of the mHMG‐CoAS gene in vivo. Immunofluorescence of transiently transfected cells demonstrated that in the presence of PPARα, mHMG‐CoAS is translocated into the nucleus. Binding to PPARα, stimulation of PPARα activity and nuclear penetration require the integrity of the sequence LXXLL in mHMG‐CoAS, a motif known to mediate the interaction between nuclear hormone receptors and coactivators. These findings reveal a novel mechanism of gene regulation whereby the product of a PPARα‐responsive gene, normally resident in the mitochondria, directly interacts with this nuclear hormone receptor to autoregulate its own nuclear transcription.