With　the　advances　in　microfluidics,　electrowetting-on-dielectric　(EWOD)　chips　have　widely　been　applied　to　various　biological　and　chemical　laboratory　protocols.　Glass-based　EWOD　chips　with　nonregular　electrodes　are　proposed,　which　allow　more　reliable　droplet　operations　and　facilitate　the　integration　of　optical　sensors　for　many　biochemical　applications.　Furthermore,　nonregular　electrode　designs　are　utilized　in　EWOD　chips,　e.g.,　interdigitated　electrodes　for　more　reliable　droplet　manipulation,　custom　shaped　electrodes　for　specific　applications　like　concentric　heating,　etc.　However,　due　to　the　technical　challenges　of　fabricating　multilayer　interconnection　on　the　glass　substrate,　e.g.,　unreliable　process　and　high　cost,　both　control　electrodes　and　wires　are　fabricated　with　a　single-layer　configuration,　which　poses　significant　challenges　to　pin　selection　for　nonregular　electrodes.　In　this　article,　we　propose　a　minimum-cost　flow-based　routing　algorithm　called　NR-Router+　that　features　efficient　and　robust　routing　for　single-layer　EWOD　chips　with　nonregular　electrodes.　To　the　best　of　our　knowledge,　this　is　the　first　work　that　overcomes　the　aforementioned　challenges.　We　construct　a　minimum-cost　flow　algorithm　to　generate　optimal　routing　paths　followed　by　a　light-weight　model　to　handle　flow　capacity.　A　grid　reduction　strategy　is　proposed　to　reduce　the　computational　overhead.　Additionally,　a　flow　collocation　algorithm　based　on　integer　linear　programming　is　presented　to　efficiently　prevent　wire　overlapping.　Experimental　results　show　that　NR-Router+　achieves　100%　routability　while　minimizing　wirelength　with　shorter　run　time.　Moreover,　NR-Router+　can　generate　mask　files　feasible　for　manufacturing　via　adjustments　of　design　parameters,　thus　demonstrating　its　robustness　and　efficiency.　©　1982-2012　IEEE.