Pulmonary hypertension (PH) at rest is a risk factor for death in patients with sickle cell anemia (SCA). Exercise echocardiography (EE) can detect latent PH. We sought to investigate the occurrence of exercise-induced abnormal response of systolic pulmonary artery pressure (SPAP) in adult patients with SCA and normal SPAP at rest, and to identify the independent predictors of this abnormal response. Forty-four adult patients with SCA and normal SPAP at rest (tricuspid regurgitant jet flow velocity [TRV] <2.5m/sec) were studied and divided into 2 groups: exhibiting normal SPAP after treadmill EE (TRV≤2.7m/sec) (G1), and exhibiting abnormal exercise-induced increase of SPAP (TRV>2.7m/sec) (G2). TRV cutoff points at rest and during EE were based on data from healthy-matched control subjects. Abnormal response of SPAP with exercise occurred in 57% of the sample (G2), with mean TRV level of 3.39±0.41m/sec (range 2.8-4.5m/sec), significantly higher than those of G1 (2.29±0.25m/sec, range 2.0-2.7m/sec; P<0.001). Multivariate analysis identified TRV value in resting conditions ≥2.25m/sec (P<0.05), left atrial volume index ≥41mL/m2 (P<0.05), and a E/e'-waves ratio ≥6.3 (P<0.05) as independent predictors of exercise-induced increase of SPAP. We concluded that adult patients with SCA and normal SPAP at rest may exhibit abnormal exercise-induced increase in SPAP, which was independently related to resting TRV levels, and indices of diastolic impairment and left ventricular filling pressure.