We compare the opto-electronic and photovoltaic properties of two diketopyrrolopyrrole (DPP) based semiconducting polymers in which the DPP unit alternates along the chain with a conjugated bis(dithienyl)phenylene (4TP) unit. The two polymers differ only in the solubilizing substituents on the thiophene rings which are either alkyl (PDPP4TP) or alkoxy (PDPP4TOP) groups. We show that alkoxy groups lower the optical band gap and increase the ionization potential compared to the alkyl groups. As a result, PDDP4TOP provides a significantly higher charge generation efficiency and concomitant higher short-circuit current, 18.0 mA cm−2 vs. 12.4 mA cm−2, compared to PDPP4TP in optimized devices with [6,6]phenyl-C71-butyric acid methyl ester ([70]PCBM) as acceptor, but a simultaneous decrease in open circuit voltage, 0.51 vs. 0.67 V. The increased current arises from a higher external quantum efficiency and a wider spectral coverage. The net result is a small increase in power conversion efficiency from 5.8% for PDPP4TP to 6.0% for the PDPP4TOP in optimized devices. The optimized processing conditions and bulk heterojunction morphology are virtually identical for both photoactive layers. The study demonstrates that the side chains enable effective method for rationally designing new photoactive semiconducting polymers.