Here, means to enhance power conversion efficiency (PCE or η) in bulk-heterojunction (BHJ) organic photovoltaic (OPV) cells by optimizing the series resistance (Rs)—also known as the cell internal resistance—are studied. It is shown that current state-of-the-art BHJ OPVs are approaching the limit for which efficiency can be improved via Rs reduction alone. This evaluation addresses OPVs based on a poly(3-hexylthiophene):6,6-phenyl C61-butyric acid methyl ester (P3HT:PCBM) active layer, as well as future high-efficiency OPVs (η > 10%). A diode-based modeling approach is used to assess changes in Rs. Given that typical published P3HT:PCBM test cells have relatively small areas (∼0.1 cm2), the analysis is extended to consider efficiency losses for larger area cells and shows that the transparent anode conductivity is then the dominant materials parameter affecting Rs efficiency losses. A model is developed that uses cell sizes and anode conductivities to predict current–voltage response as a function of resistive losses. The results show that the losses due to Rs remain minimal until relatively large cell areas (>0.1 cm2) are employed. Finally, Rs effects on a projected high-efficiency OPV scenario are assessed, based on the goal of cell efficiencies >10%. Here, Rs optimization effects remain modest; however, there are now more pronounced losses due to cell size, and it is shown how these losses can be mitigated by using higher conductivity anodes.