The effects of anode/active layer interface modification in bulk-heterojunction organic photovoltaic (OPV) cells is investigated using poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) and/or a hole-transporting/electron-blocking blend of 4,4′-bis[(p-trichlorosilylpropylphenyl)-phenylamino]biphenyl (TPDSi2) and poly[9,9-dioctylfluorene-co-N-[4-(3-methylpropyl)]-diphenylamine] (TFB) as interfacial layers (IFLs). Current–voltage data in the dark and AM1.5G light show that the TPDSi2:TFB IFL yields MDMO-PPV:PCBM OPVs with substantially increased open-circuit voltage (Voc), power conversion efficiency, and thermal stability versus devices having no IFL or PEDOT:PSS. Using PEDOT:PSS and TPDSi2:TFB together in the same cell greatly reduces dark current and produces the highest Voc (0.91 V) by combining the electron-blocking effects of both layers. ITO anode pre-treatment was investigated by X-ray photoelectron spectroscopy to understand why oxygen plasma, UV ozone, and solvent cleaning markedly affect cell response in combination with each IFL. O2 plasma and UV ozone treatment most effectively clean the ITO surface and are found most effective in preparing the surface for PEDOT:PSS deposition; UV ozone produces optimum solar cells with the TPDSi2:TFB IFL. Solvent cleaning leaves significant residual carbon contamination on the ITO and is best followed by O2 plasma or UV ozone treatment.