Strong electronic interactions can result in novel particle–antiparticle (electron–hole, e–h) pair generation effects1, which may be exploited to enhance the photoresponse of nanoscale optoelectronic devices. Highly efficient e–h pair multiplication has been demonstrated in several important nanoscale systems, including nanocrystal quantum dots2,3,4,5,6, carbon nanotubes7,8,9 and graphene10,11,12,13. The small Fermi velocity and nonlocal nature of the effective dielectric screening in ultrathin layers of transition-metal dichalcogenides (TMDs) indicates that e–h interactions are very strong14,15,16, so high-efficiency generation of e–h pairs from hot electrons is expected. However, such e–h pair multiplication has not been observed in 2D TMD devices. Here, we report the highly efficient multiplication of interlayer e–h pairs in 2D semiconductor heterostructure photocells. Electronic transport measurements of the interlayer I–V SD characteristics indicate that layer-indirect e–h pairs are generated by hot-electron impact excitation at temperatures near T = 300 K. By exploiting this highly efficient interlayer e–h pair multiplication process, we demonstrate near-infrared optoelectronic devices that exhibit 350% enhancement of the optoelectronic responsivity at microwatt power levels. Our findings, which demonstrate efficient carrier multiplication in TMD-based optoelectronic devices, make 2D semiconductor heterostructures viable for a new class of ultra-efficient photodetectors based on layer-indirect e–h excitations.