Background: The emergence of infection caused by invasive penicillinnonsusceptible (PNS) and multidrug-resistant strains of Streptococcus pneumoniae has become a worldwide concern, necessitating the epidemiologic surveillance of such strains. Objectives: One aim of this study was to identify clones of invasive PNS S pneumoniae among isolates in Riyadh, Saudi Arabia. The second aim was to compare these clones with international clones to track their spread in Saudi Arabia. Methods: The phenotypes of invasive isolates characterized as S pneumoniae were determined using susceptibility testing and serotyping (capsular test and E-test). The genotypes of PNS isolates were determined using random amplified polymorphic DNA analysis. The genetic relatedness of these local strains to the international widespread clones was investigated. Results: Of 296 S pneumoniae isolates identified using biochemical and culture characteristics, 89 (30.1%) were invasive. Susceptibility testing using the E-test revealed that 17 of the 89 invasive isolates (19.1%) were PNS. Most of the 89 isolates (89.9%) were resistant to sulfamethoxazole-trimethoprim; 32.6% and 23.6% of isolates were resistant to chloramphenicol and tetracycline, respectively. All of the isolates (100.0%) were fully susceptible to ceftriaxone and vancomycin. Capsular serotyping of the 89 isolates showed that 19A (18.0%), 613 (14.6%), 23F (13.5%), 9V (11.2%), 14 (6.7%), 19F (5.6%), and 18C (4.5%) were the most predominant serogroups/serotypes. The 17 PNS strains were confirmed on polymerase chain reaction to have penicillin resistance genes. Of these 17 strains, international clone 19A-a was the most predominant (41.2%), followed by 6B-a (17.6%), and 23F-a and 9V-a (each, 11.8%). Conclusions: The present study identified the spread of the 4 most commonPNS S pneumoniae isolates (clones)—19A, 613, 23F, and 9V-to Riyadh, but identified no new clones among patients having invasive infection with S pneumoniae in Riyadh. This study emphasizes that international PNS clones have contributed to the prevalence and spread of PNS pneumococci among the clinical isolates in Saudi Arabia.