Data from 4,727 invasive isolates of Streptococcus pneumoniae, submitted to the Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory between 1999 and 2007, were analysed to establish susceptibility profiles to penicillin, erythromycin and cefotaxime. Pneumococcal resistance to penicillin over the study period remained low, with only 0.2%, (n= 7/4,727), isolates falling into this category, (MIC great than or equal to 2 mg/l). These isolates have been sporadic, and have mainly represented serogroup 14 (ST9) and 9 (ST156). In comparison, the 'intermediate sensitivity' group, (MIC 0.12-1 mg l-1), ranged between 2-6% per year, the majority from serogroup 9 (ST156). Over the study period we found 12%, (n= 585/4,727), of isolates were erythromycin resistant, (MIC >0.5 mg l1), with the majority, (n= 467; 80%), of these isolates identified as serogroup 14 (ST9). Cephalosporin resistance, (cefotaxime MIC >1mg l-1), was found in only 0.06%, (n= 2/3,135), of isolates. Internationally recognised clones, (Pneumococcal Molecular Epidemiology Network, PMEN), accounted for 35%, (n=28/81), of the penicillin-non-susceptible isolates, and 75%, (n=248/330), of the macrolide-resistant isolates, with ST9 and ST 306 predominating. Between 1999 and 2007 we found that 11.6%, (n=18/155), of the penicillin non-susceptible isolates and 4.8%, (n=28/585), of the macrolide-resistant isolates were from serogroups not covered by the 7-valent conjugate pneumococcal vaccine in use in the UK since 2006. Susceptibility to first line antimicrobial agents for invasive pneumococcal disease, (IPD), in Scotland has remained high over the period 1999-2007.