To assess whether changes in mean cell volume (MCV) could be used as a surrogate marker of adherence, the percentage rise from the baseline MCV (%MCV rise) was compared to an independent marker of adherence, the number of days of medications dispensed in a 24-week period. Nucleoside analogues were found to differ in the extent to which they affect the MCV. The correlation between zidovudine (AZT) (30 subjects) and stavudine (D4T) (41 subjects) with adherence based on prescriptions was 0.82 (P<0.05) and 0.55 respectively (P<0.05). When adherence was categorized into 10% intervals, there was a progressive rise in the average MCV with increasing adherence that plateaus at 70% adherence. Plotting %MCV rise on time charts appears to detect those subjects with adherence of less than 70%. In conclusion, changes in MCV for HIV-positive patients taking either AZT or D4T may be a useful surrogate marker for adherence to anti-retroviral medications.