Thirty-four eastern indigo snakes ( Drymarchon couperi ) naturally infected with Cryptosporidium serpentis were randomly divided into two groups. The first group received 360 mg/kg paromomycin twice weekly in a food item for six weeks, while the second group received the food item with no treatment. Cloacal swabs were collected every two months for six months to measure C. serpentis shedding by quantitative polymerase chain reaction testing (qPCR). Snakes that were qPCR negative after six 6 months were immunosuppressed with a single dose of 4 mg/kg dexamethasone sodium-phosphate SC. These snakes were then screened by qPCR for an additional 6 months as described above. Snakes that were qPCR negative after one year of serial sampling were then re-evaluated for C. serpentis via gastric biopsy for histological and qPCR analyses. The paromomycin-treated group were significantly (p=0.008) more likely to test qPCR negative (8/17; 47%, 95% Confidence Interval [CI]: 23.2-70.7) than the control snakes (1/17; 5.8%, 95% CI: 0.01-16.9) prior to immunosuppression. However, there was no significant difference (p=0.5) in C. serpentis status following immunosuppression as only 2/17 (11.7%, 95% CI: 0.01-26.9) paromomycin-treated snakes were qPCR negative six months after immunosuppression compared to 1/17 (5.8%, 95% CI: 95% CI: 0.01-16.9) control snakes. These findings suggest that 360 mg/kg paromomycin twice weekly for six weeks in a food item is ineffective in eliminating C. serpentis in naturally infected D. couperi .