Intercropping of seedless watermelon [Citrullus lanatus (Thumb.) Matsum. & Nak.] and cotton [Gossypium hirsutum (L.)] in the eastern geographical area of South Carolina requires changes in normal crop-management programs but has the potential to improve grower profits compared with typical production of each crop separately. The alteration and timing of several normal crop-production practices for both crops can present challenges and must be well-defined for successful intercropping of watermelon and cotton in the region. Notable adjustments in production for watermelon are delayed planting date, reduced row spacing and bed width, and modification of herbicide applications. Significant changes in normal cotton production also include modification of herbicide applications, but additional considerations, such as temporal limits on side-dressed fertilizer and insecticide applications, are needed because of the raised beds and plasticulture used for watermelons and also because of labeling restrictions for pesticides across crops. Research was conducted to 1) identify modifications in standard crop-management procedures for watermelon and cotton intercropping; and 2) determine the feasibility and profitability of intercropping the crops. Although there was a slight numerical reduction in intercropped watermelon yield each year, there were no significant differences in total watermelon yield between intercropping and watermelon monoculture in any of the years. There were also no significant differences in watermelon fruit quality parameters (size, brix, hard seed, hollow heart) in any of the years. Intercropped cotton yield was significantly less than monoculture cotton yields in each of the three years. The net income from intercropping in each year was slightly less than the net income from watermelon monoculture.