Abstract Background Exercise is associated with changes in circulating B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP). However, the biological relevance of this phenomenon is poorly examined. We sought to assess determinants of absolute (Δ) and relative (Δ%) exercise-induced changes in BNP and NT-proBNP. Methods BNP ( n = 418) and NT-proBNP ( n = 478) at rest and peak exercise were measured in patients undergoing symptom-limited cycle ergometer tests. Multivariate logistic regression was performed to identify predictors of high Δ BNP/ Δ NT-proBNP and high Δ BNP/ Δ %NT-proBNP defined as their highest quartiles (Q4). Results The median (interquartile range) Δ BNP and Δ NT-proBNP was 12 (0–28) pg/ml and 7 (2–21) pg/ml respectively, and Δ %BNP and Δ %NT-proBNP was 21 (0–46) % and 7 (3–12) % respectively. Higher BNP odds ratio (OR) 3.92 per ln unit; p < 0.001 or NT-proBNP OR 4.88 per ln unit; p < 0.001 at rest was the strongest predictor of Δ BNP in Q4 (≥ 28 pg/ml) or Δ NT-proBNP in Q4 (≥ 21 pg/ml). In contrast, higher maximal work rate expressed as the percentage of the predicted value (OR 1.015 per %; p = 0.007) was the only independent predictor of Δ %BNP in Q4 (≥ 46%), and lower resting heart rate (OR 0.97 per bpm; p = 0.001) and lower age (OR 0.95 per year; p = 0.001) were the only independent predictors of Δ %NT-proBNP in Q4 (≥ 12%). Conclusions Higher ΔBNP and ΔNT-proBNP primarily reflected higher BNP and NT-proBNP plasma levels at rest. In contrast, higher Δ%BNP and Δ%NT-proBNP were associated with several prognostically favorable features, indicating that higher Δ%BNP and Δ%NT-proBNP may be markers of health rather than disease.