We report here high-precision multiple sulfur and iron isotope compositions for a series of mineralized samples from Ni-Cu-(PGE) sulfide deposits in the Archean Tati greenstone belt and the Phikwe Complex of eastern Botswana. Mineralized samples from the Phoenix and Selkirk Ni-Cu-(PGE) deposits in the Tati greenstone belt display slightly positive δ34S isotope values, ranging from 0.2 to 0.8‰ V-CDT. Δ33S values of sulfides at Phoenix and Selkirk are −0.01 to −0.08‰ V-CDT, suggesting either a dominantly mantle sulfur source or effective eradication of a crustal Δ33S anomaly through equilibration with large amounts of silicate melt. In the Selebi-Phikwe belt, a granite-gneiss terrane with abundant amphibolite lenses of either volcanic and/or intrusive nature, mineralized lower grade samples from the Phikwe, Phokoje, and Dikoloti Ni-Cu-(PGE) deposits have more variable δ34S values ranging from −3.1 to +0.3‰ and display significant mass independent anomalies (Δ33S values ranging from −0.89 to −0.27‰), suggesting that barren sulfides associated with distal or low-temperature sea-floor hydrothermal activity contributed sulfur to these deposits. Iron isotopes of sulfides from these deposits show a relatively small range of negative Δ56Fe values (−0.29 to −0.04‰), consistent with high-temperature fractionations in magmatic systems, with the exception of one sample from the Dikoloti Ni-Cu-(PGE) deposit of the Selebi-Phikwe greenstone belt, which shows a more negative δ56Fe value of −0.61‰, consistent with assimilation of sedimentary or hydrothermal sulfides rather than fractionations in high-temperature magmatic systems. Data from this study highlight the complexity and variability that characterize ore-forming processes in magmatic systems. We suggest that the presence of sulfur-bearing lithologic units in host rocks of mafic and ultramafic intrusions may not be essential toward the assessment of the prospectivity of a province to host orthomagmatic nickel sulfides. Geologic settings without any or little sulfur in the stratigraphy, which have been traditionally neglected in terms of their prospectivity, should thus be revisited and possibly reassessed considering the potential importance of external source of sulfur to generate ore deposits.