To compare antimicrobial resistance in S. Typhi and S. Paratyphi A isolates from Pakistan. Blood samples were collected through > 175 laboratory collection points in major cities and towns across the country. The study included 3,671 S. Typhi and 1,475 S. Paratyphi A isolates (2001-2006). Multidrug resistance (MDR) was defined as resistance to first-line agents co-trimoxazole, chloramphenicol and ampicillin. In total, 79.3% S. Typhi and 59.9% S. Paratyphi A were isolated from patients under 15 years of age. During the study period, the MDR rate increased in S. Typhi (34.2 to 48.5% p<0.001). Quinolone resistance (MIC> 1 microg/ml) increased in both S. Typhi (1.6 to 64.1% p<0.001) and S. Paratyphi A (0 to 47% p<0.001). The increase in the proportion of strains showing high level quinolone resistance (MIC > 4 microg/ml) was greater in S. Paratyphi A when compared to S. Typhi. Resistance to first-line drugs was higher in those <15 years of age whereas quinolone resistance was higher in older patients. Differences between S. Typhi and S. Paratyphi A, in terms of evolution of resistance to first-line agents and to quinolones, are evident in this population. The rapid increase in quinolone resistance in S. Paratyphi A when compared to S. Typhi is concerning and requires further study.