Introduction: Despite an increasing awareness that the activity of excitable membranes is determined by the underlying ionic gradients across them, and their importance in drug dependency, we were not able to identify any reports of comparing the electrolyte composition of opioid-dependent and non-addicted controls. Methods: Linear regression was used to compare clinical pathology blood results taken from 2699 opioid-dependent patients (ODP) and 5307 medical control (MC) patients on a total of 21,734 occasions for the period 1995-2015. The presence of a hepatitis C antibody test was used to separate OPD and MC patients. Results: The mean age among ODP and MC was 33.51 ± 0.16 and 37.99 ± 0.23 years, respectively (p < 0.0001). The groups were 71.5% and 54.2% male (p < 0.0001). Drug use in this cohort has been reported previously. Analysis of sodium, haemoglobin and albumin were used to exclude marked effects of haemodilution/haemoconcentration. Repeated measures linear regression against age and time showed depressed levels of bicarbonate (p < 0.0001) and potassium (p < 0.05) and elevated levels of chloride (p < 0.025) and anions (p < 0.01) in ODP in both sexes. Multiple regression in mixed-effects models showed that these effects were all worse in females (p = 0.0001). Conclusion: This data shows that opioid dependence is associated with significant changes in chloride, potassium, bicarbonate and anions in both sexes, and worse in females. This likely has implications for the electrophysiological properties of excitable membranes. It is consistent with the reported impairment of potassium-chloride exchangers in opioid dependence. Explication of the mechanisms responsible must await further studies.