Larval mussels (Family Unionidae) are obligate parasites on fish, and after excystment from their host, as juveniles, they are transported with flow. We know relatively little about the mechanisms that affect dispersal and subsequent settlement of juvenile mussels in large rivers. We used a three-dimensional hydrodynamic model of a reach of the Upper Mississippi River with stochastic Lagrangian particle tracking to simulate juvenile dispersal. Sensitivity analyses were used to determine the importance of excystment location in two-dimensional space (lateral and longitudinal) and to assess the effects of vertical location (depth in the water column) on dispersal distances and juvenile settling distributions. In our simulations, greater than 50% of juveniles mussels settled on the river bottom within 500 m of their point of excystment, regardless of the vertical location of the fish in the water column. Dispersal distances were most variable in environments with higher velocity and high gradients in velocity, such as along channel margins, near the channel bed, or where effects of river bed morphology caused large changes in hydraulics. Dispersal distance was greater and variance was greater when juvenile excystment occurred in areas where vertical velocity (w) was positive (indicating an upward velocity) than when w was negative. Juvenile dispersal distance is likely to be more variable for mussels species whose hosts inhabit areas with steeper velocity gradients (e.g. channel margins) than a host that generally inhabits low-flow environments (e.g. impounded areas).