In the present study, we conducted surveillance of the V. parahaemolyticus strains present in clinical samples from six geographical regions of Mexico (22 states) from 2004 to 2011. The serotype dominance, virulence genes, presence of pandemic O3:K6 strains, and antibiotic resistance of the isolates were investigated. In total, 144 strains were isolated from the clinical samples. Seven different O serogroups and twenty-five serovars were identified. Most clinical isolates (66%, 95/144) belonged to the pandemic clone O3:K6 (tdh+, toxRS/new+ and/or orf8+) and were detected in 20 of the 22 states. Among the pandemic clones, approximately 17.8% (17/95) of the strains cross-reacted with the antisera for the K6 and K59 antigens (O3:K6, K59 serotype). Other pathogenic strains (tdh+ and/or trh+, toxRS/new−, orf8−) accounted for 26.3%, and the nonpathogenic strains (tdh− and/or trh−) accounted for 7.6%. Antimicrobial susceptibility testing showed that most of the strains were resistant to ampicillin (99.3%) but were sensitive to most tested antibiotics. The level of multidrug resistance was 1.3%. Our results indicate that pandemic O3:K6 is present in most Mexican states, thus, constant surveillance of V. parahaemolyticus strains in diarrhea patients is a public health priority and is useful for conducting risk assessments of foodborne illnesses to prevent V. parahaemolyticus outbreaks. Overall, our observations indicate that the pandemic O3:K6 clone of V. parahaemolyticus has become a relatively stable subpopulation and may be endemically established in Mexico; therefore, constant surveillance is needed to avoid new outbreaks of this pathogen.