To compare the course of treatment in patients with symptomatic Wilson's disease (WD) receiving either D‐penicillamine (DPA) or zinc sulfate (ZS) as first‐line therapy.

In all, 143 consecutive patients diagnosed with symptomatic WD from January 2005 to December 2009, followed until December 2010, were included. The decision about first‐line therapy was made individually after discussion with the patient. Physicians had no clear preference of one drug over the other. Data were analyzed in subgroups with predominantly neurological (DPA, 35; ZS, 21) and hepatic (DPA, 36; ZS, 51) presentation of WD.

According to Kaplan–Meier analysis, neurological WD patients scheduled for DPA had a similar probability of not remaining on first‐line therapy as patients receiving ZS (20% vs. 24% at the end of follow‐up), with adjusted odds ratio (OR) of 0.9 (95% CI 0.2–3.5). In patients with hepatic WD, this probability was significantly higher for DPA (31% vs. 12%; adjusted OR 3.0, 95% CI 0.9–9.9), especially in the first 6 months. Early worsening occurred only in neurological WD patients, with no differences between both treatment groups (35% vs. 19%; OR 2.8, 95% CI 0.7–10.8). Neurological improvement and decrease of liver enzymes were achieved with similar frequency. Compliance with DPA was better in hepatic (97% vs. 80%) but not in neurological patients (91% vs. 81%). Drug adverse effects were more common on DPA (15% vs. 3%).

DPA and ZS are effective in the majority of WD patients. Neither therapy appears to be clearly superior. Therefore ZS may be considered a reasonable alternative to DPA as a first‐line therapy.