Gestational trophoblastic disease (GTD) is an uncommon but highly treatable condition. There is limited local evidence to guide therapy. To report the experience of a statewide registry in the treatment of low-risk gestational trophoblastic neoplasia (GTN) over a 20-year period. A retrospective review of the prospectively maintained GTD registry database was conducted. There were 144 patients identified with low-risk GTN, of which 115 were analysed. Patient demographics, treatment details and outcomes, including development of resistance, toxicity or relapse were reviewed. The incidence of GTD was 2.6/1000 live births. There was 100% survival. The mean time from diagnosis to commencing treatment was 1.9 days (range 0-29 days). Seventy-seven percent of patients treated with methotrexate achieved complete response. Thirteen patients (11.3%) required multi-agent chemotherapy, for the treatment of resistant or relapsed disease. There was a higher rate of treatment resistance in those with World Health Organization (WHO) risk scores 5-6 (odds ratio (OR) 6.56, 95% CI 1.73-24.27, P = 0.005) and those with pre-treatment human chorionic gonadotropin >10 000 (OR 4.00 95% CI 1.73-24.27 P = 0.007). Four patients (3.5%) were diagnosed with choriocarcinoma after commencing treatment. Nine patients (7.8%) had successful surgical treatment for GTN, both alone and in combination with chemotherapy. The relapse rate was 4.3%; all were treated successfully with a combination of chemotherapy and surgery, and 93.9% of patients completed follow up through the registry. Methotrexate is a highly effective treatment for low-risk GTN, especially with WHO risk score ≤4. The optimal treatment for those with risk scores of 5-6 requires further investigation.