Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when co-administered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 non-pregnant and 45 pregnant women treated with SP-AZI (n=15 in each group) and SP-chloroquine (n=30 in each group) were analyzed. Population non-linear mixed effects pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX) and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX and NASDOX by 48%, 29% and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46%, 99%) and NASDOX (46%). Co-administration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design including the use of an early postpartum follow-up study rather than a non-pregnant comparator group. Simulations based on the final population model demonstrated that, compared with conventional single-dose SP in non-pregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials employing recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings, and consideration given to using increased doses in future trials.