The purpose of this study is (1) to evaluate skeletal muscle magnesium (Mg) and potassium (K) during treatment with cisplatin; (2) to evaluate the predictive value of plasma (P)-Mg for intracellular Mg during cisplatin treatment; and (3) to evaluate whether changes in intracellular K influence skeletal muscle Na,K-ATPase. In all, 65 patients had a needle muscle biopsy obtained before and 26 patients both before and after cisplatin treatment. Biopsies were analysed for Mg, K, and Na,K-ATPase concentrations, and P-Mg and P-K determined. Treatment with a total dose of ≈500mg (270 mg m-2 surface area) cisplatin over 80 days was associated with reductions in muscle [Mg] (95% CI) (8.95 (8.23-9.63) to 7.76 (7.34-8.18) μmol g-1 wet wt. (P < 0.01), and muscle [K] (90.81 (83.29-98.34) to 82.87 (78.74-87.00) μmol g-1 wet wt. (P < 0.05), as well as in P-Mg 0.82 (0.80-0.85) to 0.68 (0.64-0.73) mmol l-1 (P < 0.01 but not in P-K (4.0 (3.8-4.1) vs 3.8 (3.7-4.0) mmol l-1). No simple correlations were observed between P-Mg and muscle [Mg], or between P-K and muscle [K], either before (n = 65) or after (n = 26) treatment with cisplatin. The changes in [Mg] and [K] were not associated with changes in the muscle Na,K-ATPase concentration. Following treatment with cisplatin, an ≈ 15% decline in P-Mg was accompanied by an ≈ 15% loss of muscle [Mg], as well as an ≈ 10% reduction of muscle [K] and fatigue and muscle weakness previously ascribed to hypomagnesaemia may therefore also be well explained by muscle K depletion observed despite normal levels of P-K. There was no correlation between P-Mg and SM-Mg or between P-K and SM-K. Thus, P-Mg and P-K are not reliable indicators for Mg and K depletion during treatment with cisplatin. However, the majority of patients will present Mg and K depletion after cisplatin therapy and of these only very few patients will present a low P-Mg or P-K. Therefore, routine supplementation should be considered in all patients receiving cisplatin.