Hydrangea macrophylla is the most popular species in the genus Hydrangea because of its large and brightly colored inflorescences. Since the early 1900s, numerous cultivars with showy flowers have been selected. Although many H. macrophylla cultivars have been developed, cold hardiness is still the major limitation to their outdoor use. Hydrangea arborescens is a small attractive shrub or subshrub native to northeastern parts of the United States, which is valued for its hardiness. Interspecific breeding of H. arborescens and H. macrophylla has been tried, but putative hybrid seedlings either died at an early stage or were not verified. We made successful hybridizations between H. macrophylla ‘Blue Diamond’ and H. arborescens ‘Annabelle’ and used in vitro ovary culture to produce viable plants. Hybrids were intermediate in appearance between parents, but variable in leaves, inflorescences, and flower color. The success of this hybridization was confirmed by six simple sequence repeat (SSR) genetic markers. The maternal chromosome number was 36, and the paternal number was 38. Chromosome counts of hybrids indicated that nearly half of them were aneuploids. Male fertility of progeny was evaluated by fluorescein diacetate staining of pollen. Twelve out of 14 hybrids (85.7%) had male fertility. We documented the first flowering progeny of H. macrophylla and H. arborescens, suggesting an effective beginning to a cold hardiness breeding program.