On the urgent quest for green energy vectors, the generation of hydrogen by water splitting with sunlight occupies a preeminent standpoint. The highest solar-to-hydrogen (STH) efficiencies have been achieved with Photovoltaic-Electrochemical (PV-EC) systems. However, most of the PV-EC water splitting devices need to work at extreme conditions, such as in concentrated solutions of HClO4 or KOH, or under highly concentrated solar illumination. In this work, a molecular catalyst-based anode is incorporated for the first time in a PV-EC configuration, achieving an impressive 21.2% STH efficiency at neutral pH. Moreover, as opposed to metal oxidebased anodes, the molecular catalyst-based anode allows working with extremely small catalyst loadings (< 16 nmol/cm2) due to a well defined metallic center, which is responsible for the fast catalysis of the reaction in the anodic compartment. This work paves the way of integrating molecular materials in the efficient PV-EC water splitting systems.