A prospective in vitro survey of Gram-negative isolates obtained from patients hospitalized in intensive care units in 10 Boston teaching hospitals was undertaken to document current susceptibility patterns and analyze patterns of cross-resistance. One thousand and five isolates were obtained, 18% were pseudomonas, 18% Escherichia coli, 13% klebsiella, and 22% were in the enterobacter, citrobacter, serratia group. Cross-resistance among beta-lactams and beta-lactamase inhibitors was common for species with a potential to produce the type I inducible beta-lactamase (p less than 0.01). In contrast, resistance to imipenem was not associated with cross-resistance. Ciprofloxacin and netilmicin also remained active. Clinical observations of the development of cross-resistance to the beta-lactams in enterobacter and citrobacter infections in four patients (two bacteremias and two wound infections) seen in one institution confirm these in vitro findings. Unanswered questions remain regarding the frequency of beta-lactam cross-resistance, the most likely sites of occurrence and the overall clinical significance. Clinicians should be aware of the potential selection of type-I beta-lactamase hyperproducers by the use of second or third generation cephalosporins or related beta-lactam agents.