Lumber grade rules address well-spaced single-knot and combination-knot sizes. Information is lacking, however, with respect to multiple knots in close proximity. The term “well-spaced” appears to lack quantitation. This research investigates the effect that knots in close proximity (not necessarily combination knots) have on the strength properties of southern yellow pine (SYP; Pinus spp.) lumber. This study attempts to use a statistical model to determine the modulus of rupture (MOR) for SYP having multiple knots in close proximity using variables including the knot diameter (KD), amount of clear wood (CW) present, knot area (KA), and modulus of elasticity (MOE) of the lumber. This study investigated specimens of 2 by 4-inch SYP dimensional lumber exhibiting multiple knots in close proximity. The basic density (D) was determined by dividing the entire specimen weight by its volume. Third-point bending tests were used in flatwise orientation to quantify the MOR and MOE. There were significant correlations among all parameters analyzed. Multiple regression analysis with one dependent variable, MOR, and three independent variables, KD, MOE, and D, resulted in a coefficient of determination value (r2) of 0.702. When using only the MOE to predict MOR, an r2 value of 0.564 was found.