Dissimilar metal resistance spot welds, critical to the manufacture of medical devices, typically form brittle intermetallic compounds that are prone to failure. Here, a case study of biocompatible metals platinum and niobium using advanced analytical techniques is presented. It describes the variation of properties and microstructure using microresistance spot welding under four conditions, including a legacy process and processing conditions optimized by design of experiments. Adjustments to the electrode force, welding current, surface roughness, and pulse duration and exchanging the platinum anode contact for a cathode result in a joint with less porosity and greater uniformity in the thickness, chemistry, and microstructure of the fusion zone. The optimized microstructure contains fewer defects, with increased plasticity under deformation and a more uniform microstructure reducing the propensity for failure and variability between welds. Extensive analysis with optical, scanning electron, transmission electron microscopy coupled with nano- and micromechanical testing (such as micropillar compression) was used to characterize the weld zone.