Implant debris remains the major factor limiting the longevity of total joint replacements. Whether soluble implant debris of Zr and Nb containing implant alloys constitute a greater risk than other implant metals remains unknown. We evaluated the relative effects of soluble forms of Zr+4 and Nb+5 (0.001–10.0 mM) relative to Cr+3, Mo+5, Al+3, Co+2, Ni+2, Fe+3, Cu+2, Mn+2, Mg+2, Na+2, and V+3 chloride solutions on human peri-implant cells (i.e., osteoblast-like MG-63 cells, fibroblasts, and lymphocytes). Metals were ranked using a 50% decrease in proliferation and viability to determine toxic concentrations. Lymphocytes, fibroblasts, and osteoblasts were, generally, similarly affected by metals where the most toxic metals, Co, Ni, Nb, and V required 1.0 mM challenge to produce toxicity. Overall, Co and V were the most toxic metals tested, thus Zr and Nb containing implant alloys would not likely be more toxic than traditional implant alloys. Below concentrations of 0.1 mM, neither Zr nor Nb reduced osteoblast, lymphocyte, or fibroblast proliferation. Zr was generally an order of magnitude less toxic than Nb to lymphocytes, fibroblasts, and osteoblasts. Our results indicated that soluble Zr and Nb resulting from implant degradation likely act in a metal- and concentration-specific manner capable of producing adverse local and remote tissue responses to the same degree as metals from traditional implant alloys, e.g., Ti-6Al-4V (ASTM F 138) and Co-Cr-Mo alloys (ASTM F 75).