In inductively coupled plasma mass spectrometry, the most abundant Ca isotope ( ⁴⁰Ca) suffers from isobaric interference with argon, hindering the potential for low detection limits of Ca. A powerful approach is to remove the interference by using a reaction gas in a reaction cell. Ammonia (NH ₃) has proven to be an effective reaction gas by process of a charge transfer reaction. However, NH ₃ is highly corrosive and toxic and cannot remove isobaric ⁴⁰ K. Therefore, this work proposes the use of nitrous oxide (N ₂O) to mass shift the target analyte ⁴⁰Ca to ⁴⁰Ca ¹⁶O ⁺ as a non-corrosive and non-toxic alternative. Instrument performance testing demonstrated that N ₂O was capable of reaching equivalent detection limits (0.015 ng g ⁻¹) and background equivalence concentrations (0.041 ng g ⁻¹) to that of NH ₃ and limited by the blank only. Further investigation of matrix interferences with synthetic standards highlighted that the N ₂O approach supports the separation of potassium (K) and magnesium (Mg)–based interferences at tested concentrations of more than 600 times and almost 800 times higher than Ca respectively, whereas NH ₃ was found to only support the removal of Mg. This work highlights a clear advantage of N ₂O for low-level Ca determinations with high matrix loads, as well as compatibility with other instrumentation sensitive to corrosion that supports reaction cell technology. Graphical abstract: [Figure not available: see fulltext.].