Minimizing neppiness, neps, seed coat fragments, and motes in ginned cotton (Gossypium hirsutum L.) fibers is one of the keys to keep US fibers competitive in the global market. Forty-eight F2 hybrids derived from crosses between 12 exotic germplasm lines (male parents), i.e., six Species Polycross (SP) and six John Cotton lines, and four elite germplasm lines (female parents) were evaluated to detect combining ability for the neppiness traits. F2 hybrids and parents were planted at two locations with four and three replicates each in 2008 and 2009. Neps and seed coat fragments were measured using Advanced Fiber Information System. Significant general combining ability (GCA) effects were observed for most neppiness traits. Additive effects were more important than nonadditive effects for neps, seed coat neps (SCN), and motes. Correlation (r = 0.52) between increased nep count and increased short fiber content (SFCn) implied a possibility for simultaneous improvement of these two traits. In contrast, correlation (r = -0.50) between nep count and fineness implied an antagonistic relationship between the two properties in selection. MD15 was the best female parent with negative GCA effects for neppiness traits and SFCn. SP156 was the best general combiner with favorable GCA effects for neppiness traits and other fiber properties with positive GCA effect for lint yield. Results provide evidence for the possibility of simultaneous genetic improvement of multiple neppiness traits with lint yield and other fiber properties in Upland cotton using SP156 as parent.