Orthostatic hypotension (OH) and vitamin B12 deficiency are common disorders in older people. Several case series have reported an association between vitamin B12 deficiency and OH. The effect of vitamin B12 replacement on this dysfunction has not been studied. We prospectively studied responses to head up tilt in patients over 70 years with vitamin B12 deficiency (intervention group) and compared their responses after replacement to those of matched patients with idiopathic OH and normal serum vitamin B12 concentrations (control group). Blood pressure (BP), heart rate (HR) and systemic vascular resistance (SVR) changes during orthostatic stress were evaluated using digital artery photoplethysmography. Eight patients and eight controls were studied. Initial head up tilt produced a mean BP decrease of 44/29 mmHg (s.e.m. 4/4 mmHg) in the intervention group and 33/12 mmHg (s.e.m. 3/2 mmHg) in the control group. Repeat head up tilt 6 months after vitamin B12 replacement produced a mean BP decrease of 15/9 mmHg (s.e.m. 5/2 mmHg) in the intervention group. The mean decrease in the control group was 30/12 mmHg (s.e.m. 2/2 mmHg). The difference in BP decreases between groups was statistically significant for both systolic and diastolic BP (p < 0.001 for both systolic BP and diastolic BP). Mean SVR in the intervention group decreased by 658 dynes/cm5/sec (s.e.m. 74 dynes/cm5/sec) during initial head up tilt. Mean SVR during repeat head up tilt decreased by 79 dynes/cm5/sec (s. e. m. 12 dynes/cm5/sec). Mean SVR in the control group decreased by 158 dynes/cm5/sec (s. e. m. 10 dynes/cm5/sec) during initial head up tilt and by 258 dynes/cm5/sec (s. e. m. 31 dynes/cm5/sec). The difference in SVR changes between groups was statistically significant (p = 0.02). We conclude that replacing vitamin B12 in older patients with vitamin B12 deficiency is associated with improved orthostatic tolerance to head up tilt.