To compare the efficacy of 5-fluorouracil (5-FU) with mitomycin C (MMC) in preventing pterygium recurrence when used as an adjuvant following pterygium excision with conjunctival autograft. Low-dose MMC combined with conjunctival autograft is an effective treatment for preventing recurrence following pterygium excision, but safety, cost, and availability limit its use in developing countries. There is a paucity of data on the efficacy of 5-FU when used in Africa as an adjuvant to conjunctival autograft following pterygium excision. This is a randomized controlled prospective trial using either 50 mg/ml 5-FU or 0.01% MMC. Eighty eyes of 80 subjects were studied. Forty-six subjects with a mean age 49.8 ± 13.8 years were treated with 5-FU (USD 13.0 per unit), while 34 patients with a mean age 51.9 ± 12.1 years were treated with MMC (USD 20.0 per unit). There was no significant difference in mean age between the two groups (p = 0.48). The ratio of male to female patients in both groups was similar at 0.92:1 for the 5-FU group and 1:1 for the MMC group (p = 0.85). Mean follow-up period was 35.2 ± 29.1 weeks. Recurrence rate in the 5-FU group was 8.7% compared to 11.8% in the MMC group (recurrence risk ratio = 0.71, 95% CI 0.17-3.1, p = 0.7). One patient from the MMC-treated group had corneoscleral melting. Other complications were mild and not sight threatening. In the prevention of pterygium recurrence, 5-FU appears to compare favorably with low-dose MMC when used as an adjuvant following pterygium excision and conjunctival autograft. Further studies are required to assess the long-term effect of using 5-FU in such cases.