Isotopic systems found in Pb-Zn deposits respond in different ways to the influences of host rock and of seawater: Pb is controlled only by source rocks, whereas Sr and S have influences from both source rocks and seawater. Combining these systems has the potential of allowing the differentiation of these influences. Pb isotopic data from Chiapas and Cuba suggest mixing between non-radiogenic and radiogenic sources for both MVT and SEDEX deposits. Modern mid-ocean ridge deposits can also be modeled as mixing of two end-members on Pb plots. A non-radiogenic source dominates deposits of sediment-free ridges, whereas a radiogenic source is found most strongly in deposits of ridges with thick sediment cover. Ancient SEDEX deposits also show linear arrays consistent with two-component mixing, but are displaced from the modern line to significantly higher ²⁰⁸Pb and ²⁰⁷Pb values. The higher ²⁰⁸Pb probably reflects more involvement of Th-enriched lower continental crust, and the higher ²⁰⁷Pb reflects more older continental and less oceanic material in the source rocks. Sr isotopes are controlled by both underlying rocks and degree of interaction with seawater. ⁸⁷Sr/⁸⁶Sr and ²⁰⁸Pb/²⁰⁴Pb are strongly correlated for modern deposits (r²=0.86), suggesting that the relative contribution of seawater and rock Sr is roughly constant. Ancient deposits, however, separate into two groups, one with relatively radiogenic Sr (Meggen, Rammelsberg and Jason) and one with much less radiogenic Sr compared to Pb (Red Dog and W. Cuba). We interpret the first group as rock-dominated for Sr and the second as having a larger seawater component. Sulfur isotopes are also distinct, with the radiogenic deposits showing only a 6 permil spread from seawater compared to16 permil for the less radiogenic deposits. The small fractionation for the radiogenic group indicates closed-system sulfate reduction and hence lower water/rock ratios, which allowed the rock Sr to dominate the isotopic signature. The strong fractionation for the non-radiogenic deposits indicates more open system reaction, which allowed a larger seawater contribution to the Sr isotopic signature. Thus a comparison of the three isotopic systems allows us to rank SEDEX deposits, at least qualitatively, in order of increasing seawater influence and of increasing continental influence.