Background <p>Higher intakes of total and animal-source protein during infancy have been associated with higher body mass index (BMI) z scores in childhood.</p> Objective <p>We examined the association of substituting protein with fat or carbohydrate intake, and the substitution of protein subtypes at 9 months of age with BMI z-scores and overweight status in children at 5 years of age.</p> Methods <p>This study involved a secondary analysis of data from the Melbourne InFANT program, a 15-month infancy obesity prevention intervention, with additional follow-ups conducted without intervention when children were aged 3.5 and 5 years. Data of 345 children who completed the 9-month, and 5-year follow-ups were analysed. Dietary intake at 9 months was assessed using three 24-h recalls. BMI z-score was measured at 9 months and 5 years of age. Multivariable linear and logistic regression models with adjustment for potential confounders examined the associations between macronutrient and protein subtype substitutions at 9 months and changes in BMI z-score or overweight status at 5 years.</p> Results <p>Substitution of 5%E or 100 kJ protein intake with carbohydrate intake at age 9 months was associated with a 0.16-unit (95% CI: −0.30, −0.02) or 0.11-unit (95% CI: −0.19, −0.03) decrease in BMI z-score at 5 years. Similarly, replacing 5%E or 100 kJ of protein intake with fat intake was associated with a 0.16-unit (95% CI: −0.29, −0.02) or 0.11-unit (95% CI: −0.19, −0.03) decrease in BMI z-score. There was no evidence of an association between substitution of protein with fat or carbohydrate intake and overweight status (<i>P</i> &gt; 0.05). Replacement of animal protein with plant or dairy protein was also not significantly associated with BMI z-score or overweight status.</p> Conclusions <p>Substituting protein with carbohydrate or fat intake in infancy was inversely associated with BMI z-score in early childhood. The present study supports the need to discourage excessive protein intake during infancy.</p>