Between August and October 2013, the number of new kalazar cases increased from 15 to 83 in Upper Nile.
Most of the cases were recorded in Malakal County, UNOCHA said.
Last year, 23 cases were recorded over the same period.
Health partners are supporting Malakal Teaching Hospital with medical staff and supplies.
They are also conducting assessments in several locations to diagnose new cases and investigate the reasons for the increase in infections.
Kalazar is a parasitic disease transmitted by sand flies that can be fatal if left untreated.