Huntington's disease is caused by polyglutamine expansion (exp) in huntingtin (Htt). Htt‐associated protein‐1 (HAP1) was the first identified Htt‐binding partner. The type 1 inositol (1,4,5)‐trisphosphate receptor (InsP₃R1) is an intracellular Ca²⁺ release channel that plays an important role in neuronal function. Recently, we identified a InsP₃R1–HAP1A–Htt ternary complex in the brain and demonstrated that Htt^exp, but not normal Htt, activates InsP₃R1 in bilayers and facilitates InsP₃R1‐mediated intracellular Ca²⁺ release in medium spiny striatal neurons [MSN; T.‐S. Tang et al. (2003) Neuron, 39, 227–239]. Here we took advantage of mice with targeted disruption of both HAP1 alleles (HAP1 –/–) to investigate the role of HAP1 in functional interactions between Htt and InsP₃R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Htt^exp on InsP₃R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca²⁺ levels resulting from Htt or Htt^exp overexpression; (iv) HAP1 facilitates potentiation of InsP₃R1‐mediated Ca²⁺ release by Htt^exp in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP₃R1.