The study was done with the aim to find out the effect of prophylactic chemotherapy on regression pattern of serum β-HCG and on the incidence of persistent trophoblastic disease in patients with high risk complete hydatidiform mole. Methods Out of 43 patients of complete hydatidiform mole diagnosed over a period of 1 year, 24 were categorised as high risk on the basis of Curry criteria. After suction and evacuation , 12 out of 24 high risk patients were given prophylactic chemotherapy in the form of low dose oral methotrexate (chemoprophylaxis group) and other 12 high risk patients served as control (control group) . Follow up was done clinically and with serum β-HCG levels. Results All 12 patients of chemoprophylaxis group had benign regression of the disease and none of them developed persistent trophoblastic disease. In control group, 4 (33%) out of 12 patients had persistent trophoblastic disease. There was rapid fall of serum β-HCG in chemoprophylaxis group in mean time of 7.3 weeks as against 9.7 weeks in control group. No serious toxicity was observed with chemotherapy. Conclusion Prophylactic chemotherapy reduces the occurrence of persistent trophoblastic disease in high risk hydatidiform mole patients without causing any life threatening toxicity.