Abstract Cross-fostering is a practice commonly used in the swine industry to equalize litter sizes, however, there is limited understanding of the optimum cross-fostering methods that will maximize piglet preweaning growth and survival. This study evaluated the effects of within-litter variation in birth weight after cross-fostering on piglet preweaning mortality (PWM) and weaning weight (WW) using litters of 15 piglets. A hierarchical incomplete block design was used (blocking factors: day of farrowing and sow parity, body condition score, and number of functional teats) with a 3 × 2 factorial arrangement of treatments: 1) Birth Weight Category (BWC): Light (<1.0 kg), Medium (1.0 to 1.5 kg), or Heavy (1.5 to 2.0 kg); 2) Litter Composition: UNIFORM (all 15 piglets in each litter of the same BWC), or MIXED (five piglets in each litter from each BWC, i.e., five Light, five Medium, and five Heavy piglets). At 24 h after birth, piglets were weighed and randomly allotted to litter composition treatments from within BWC. The experimental unit was five piglets of the same BWC; there were three experimental units within each Litter Composition treatment litter. There were 17 blocks, each of six litters (one UNIFORM litter of each BWC; three MIXED litters) and 51 replicates (three replicates per block of six litters) for a total of 102 cross-fostered litters and 1,530 piglets. Piglets were weaned at 19.7 ± 0.46 d of age; WW and PWM were measured. PROC GLIMMIX and MIXED of SAS were used to analyze PWM and WW, respectively. Models included BWC, Litter Composition, the interaction, and replicate within the block. There were BWC by Litter Composition treatment interactions (P ≤ 0.05) for PWM and WW. Preweaning mortality was greater (P ≤ 0.05) for Light piglets in MIXED than UNIFORM litters. In contrast, for Heavy piglets, PWM was greater (P ≤ 0.05) and WW was lower (P ≤ 0.05) in UNIFORM than MIXED litters. Medium piglets had similar (P > 0.05) PWM and WW in UNIFORM and MIXED litters. The results of this study, which involved large litter sizes typical of current commercial production, suggested that for piglet survival to weaning, using cross-fostering to form litters of piglets of similar birth weight was beneficial for light piglets, detrimental for heavy piglets, and neutral for medium piglets.